Ebook Egan''s fundamentals of respiratory care (11/E): Part 2

SECTION IV

REVIEW OF
CARDIOPULMONARY
DISEASE


CHAPTER 

24 

Pulmonary Infections
SARAH A. LONGWORTH, STEVEN K. SCHMITT, AND DAVID L. LONGWORTH

CHAPTER OBJECTIVES
After reading this chapter you will be able to:
◆ State the incidence and economic impact of pneumonia in the United States.
◆ Discuss the current classification scheme for pneumonia and be able to define hospital-acquired pneumonia,
health care–associated pneumonia, and ventilator-associated pneumonia.
◆ Recognize the pathophysiology and common causes of lower respiratory tract infections in specific clinical
settings.
◆ List the common microbiologic organisms responsible for community-acquired and nosocomial pneumonias.
◆ Describe the clinical and radiographic findings seen in patients with pneumonia.
◆ Describe risk factors associated with increased morbidity and mortality in patients with pneumonia.
◆ State the criteria used to identify an adequate sputum sample for Gram stain and culture.
◆ Describe the techniques used to identify the organism responsible for nosocomial pneumonia.
◆ List the latest recommendations regarding empiric and pathogen-specific antibiotic regimens used to treat
various types of pneumonia.
◆ Discuss strategies to prevent pneumonia.
◆ Describe how the respiratory therapist aids in diagnosis and management of patients with suspected
pneumonia.

CHAPTER OUTLINE
Classification
Pathogenesis
Microbiology
Clinical Manifestations
Chest Radiograph
Risk Factors for Mortality and Assessing the Need
for Hospitalization
Diagnostic Studies
Community-Acquired Pneumonia
Health Care–Associated Pneumonia, HospitalAcquired Pneumonia, and Ventilator-Associated
Pneumonia
Antibiotic Therapy
Community-Acquired Pneumonia
Health Care–Associated Pneumonia, HospitalAcquired Pneumonia, and Ventilator-Associated
Pneumonia

Prevention
Community-Acquired Pneumonia
Health Care–Associated Pneumonia, HospitalAcquired Pneumonia, and Ventilator-Associated
Pneumonia
Tuberculosis
Epidemiology
Pathophysiology
Diagnosis
Precautions
Treatment
Role of the Respiratory Therapist in Pulmonary
Infections

KEY TERMS
antibiotic therapy
atypical pathogens
community-acquired pneumonia
fomites

494

health care–associated pneumonia
hospital-acquired pneumonia
lower respiratory tract infection
nosocomial pneumonia

pneumonia
tuberculosis
ventilator-associated pneumonia


Pulmonary Infections  •  CHAPTER 24



I

nfection involving the lungs is termed pneumonia or
lower respiratory tract infection (LRTI) and is a common
clinical problem in the practice of respiratory care. Today,
pneumonia remains a major cause of morbidity and mortality
in the United States and worldwide. Each year, 5 million people

die from pneumonia worldwide. Five million cases of pneumonia occur annually in the United States, of which approximately
1.1 million require hospitalization at a projected yearly cost of
more than $20 billion.1 Pneumonia is the ninth leading cause
of death in the United States and the leading cause of infectionrelated mortality.2

CLASSIFICATION
Pneumonia can be classified based on the clinical setting in
which it occurs (Table 24-1). This classification is useful because
it predicts the likely microbial causes and guides empiric antimicrobial therapy while a definitive microbiologic diagnosis is
awaited. (The term empiric therapy refers to treatment that is

TABLE 24-1 
Classifications and Possible Causes of Pneumonia
Classification

Likely Organisms

Community-Acquired: Acute
Typical
Streptococcus pneumoniae
Haemophilus influenzae
Moraxella catarrhalis
Staphylococcus aureus
Atypical
Legionella pneumophila
Chlamydophila pneumoniae
Mycoplasma pneumoniae
Viruses
Coxiella burnetii
Community-acquired:

Mycobacterium tuberculosis
Chronic
Histoplasma capsulatum
Blastomycosis dermatitidis
Coccidioides immitis
Health care-associated
Mixed aerobic and anaerobic mouth flora
S. aureus
Enteric gram-negative bacilli
Influenza
Mycobacterium tuberculosis
Immunocompromised
Pneumocystis jiroveci
host
Cytomegalovirus
Aspergillus species
Cryptococcus neoformans
Reactivation tuberculosis or
histoplasmosis
Nosocomial
Aspiration
Health care-associated
Ventilator-associated

Mixed aerobes and anaerobes,
gram-negative bacilli
S. aureus
Pseudomonas aeruginosa
Acinetobacter species
Enterobacter species

Klebsiella species
Stenotrophomonas maltophilia
S. aureus

495

initiated based on the most likely cause of infection when the
specific causative organism is still unknown.)
Community-acquired pneumonia (CAP) can be divided
into two types—acute and chronic—based on its clinical presentation. Acute pneumonia presents with sudden onset over a
few hours to several days. The clinical presentation may be
typical or atypical, depending on the pathogen. The onset of
chronic pneumonia is more insidious, often with gradually escalating symptoms over days, weeks, or months.
Pneumonia acquired in health care settings is often caused
by microorganisms different from those that cause CAP. Previously termed nosocomial pneumonia, this clinical entity has
been further classified as health care–associated pneumonia
(HCAP), hospital-acquired pneumonia (HAP), and ventilatorassociated pneumonia (VAP).3 HCAP is defined as pneumonia
occurring in any patient hospitalized for 2 or more days in the
past 90 days in an acute-care setting or who in the past 30 days
has resided in a long-term care or nursing facility; attended a
hospital or hemodialysis clinic; or received intravenous antibiotics, chemotherapy, or wound care. HAP is defined as an LRTI
that develops in hospitalized patients more than 48 hours after
admission and excludes community-acquired infections that
are incubating at the time of admission. VAP is defined as an
LRTI that develops more than 48 to 72 hours after endotracheal
intubation.
HAP is a common clinical problem and represents the
second most common nosocomial infection in the United
States, accounting for 15% to 22% of all such infections.4-6
Current estimates suggest that more than 150,000 individuals

develop HAP each year. HAP increases hospital length of stay 7
to 9 days at an average incremental per-patient cost of $40,000.
In selected populations, such as patients in the intensive care
unit (ICU) and bone marrow transplant recipients, the crude
mortality rate from HAP may approach 30% to 70%, with
attributable mortality of 33% to 50%. Certain microorganisms,
such as Pseudomonas aeruginosa and Acinetobacter species, are
associated with higher rates of mortality.7

PATHOGENESIS
Six pathogenetic mechanisms may contribute to the development of pneumonia (Table 24-2). Knowledge of these mechanisms is important to both the understanding of the various
disease processes and the formulation of effective strategies
within the hospital to minimize nosocomial spread. Inhalation
of infectious particles is a common route of inoculation; this
method of acquiring an infection occurs with pulmonary
tuberculosis and justifies the policy of respiratory isolation
for patients with suspected or proved tuberculosis who are
coughing.
Aspiration of oropharyngeal secretions is the second mechanism that may contribute to the development of LRTI.
Healthy individuals may aspirate periodically, especially during
sleep. Aspiration of even a small volume of oropharyngeal
secretions, which can be colonized with potential pathogens
such as Streptococcus pneumoniae and Haemophilus influenzae,


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SECTION IV  •  Review of Cardiopulmonary Disease

TABLE 24-2 

Pathogenetic Mechanisms Responsible for
the Development of Pneumonia
Mechanism of Disease

Examples of Specific Infections

Inhalation of aerosolized
infectious particles

Tuberculosis
Histoplasmosis
Cryptococcosis
Blastomycosis
Coccidioidomycosis
Q fever
Legionellosis
Community-acquired bacterial
pneumonia
Aspiration pneumonia
Hospital-acquired pneumonia
Ventilator-associated pneumonia
Hospital-acquired pneumonia
Ventilator-associated pneumonia
Mixed anaerobic and aerobic
pneumonia from
subdiaphragmatic abscess
Amebic pneumonia from rupture
of amebic liver abscess into the
lung
Staphylococcus aureus

pneumonia arising from
right-sided bacterial endocarditis
Parasitic pneumonia:
Strongyloidiasis, ascariasis,
hookworm
Pneumocystis jiroveci pneumonia
Reactivation tuberculosis
Cytomegalovirus

Aspiration of organisms
colonizing the oropharynx

Direct inoculation of organisms
into the lower airway
Spread of infection to the
lungs from adjacent
structures

Spread of infection to the lung
through the blood

Reactivation of latent infection,
usually resulting from
immunosuppression

may contribute to development of CAP. Certain patient populations are at risk for large-volume aspiration, such as patients
with impaired gag reflexes from narcotic use, alcohol intoxication, or prior stroke. Aspiration also may occur after a seizure,
cardiac arrest, or syncope.
Aspiration seems to be the major mechanism responsible for
the development of some types of mixed aerobic and anaerobic,

gram-negative, and staphylococcal HAPs. In intubated patients,
chronic aspiration of colonized secretions through a tracheal
cuff has been linked to the subsequent occurrence of pneumonia,4 which led to the development of strategies to prevent HAP,
such as continuous suctioning of subglottic secretions in
mechanically ventilated patients and elevation of the head of
the bed.8,9
Direct inoculation of microorganisms into the lower airway
is a less common cause of pneumonia. In mechanically ventilated patients who undergo frequent suctioning of lower airway
secretions, passage of a suction catheter through the oropharynx may result in inoculation of colonizing organisms into the
trachea and subsequent development of VAP.
Contiguous spread of microorganisms to the lungs or pleural
space from adjacent areas of infection, such as subdiaphragmatic or liver abscesses, is an infrequent cause of pneumonia.
This may occur in patients with pyogenic or amebic liver

abscesses involving the dome of the liver in whom rupture of
the abscess through the diaphragm leads to the development of
pulmonary infection or empyema.
Hematogenous dissemination is the spread of infection
through the bloodstream from a remote site; it is an uncommon
cause of pneumonia. It may occur in the setting of right-sided
bacterial endocarditis, in which fragments of an infected heart
valve break off and embolize through the pulmonary arteries to
the lungs, producing either pneumonia or septic pulmonary
infarcts. Certain parasitic pneumonias, including strongyloidiasis, ascariasis, and hookworm, arise through hematogenous dissemination. In such cases, migrating parasite larvae travel to the
lungs through the bloodstream from remote sites of infection,
such as the skin or the gastrointestinal (GI) tract.
Pneumonia may develop when a latent infection, acquired
earlier in life, is reactivated. This may occur for no apparent
reason, as in the case of reactivation pulmonary tuberculosis.
However, reactivation is usually attributable to the development

of cellular immunodeficiency, as is the case with Pneumocystis
jiroveci (previously called Pneumocystis carinii) pneumonia. In
developed countries, most healthy individuals have acquired
P. jiroveci by age 3 years and show serologic evidence of prior
infection. The organism remains dormant in the lung but may
reactivate later in life and produce pneumonia in individuals
with compromised cell-mediated immunity, such as patients
with human immunodeficiency virus (HIV) infection or recipients of long-term immunosuppressive therapy. Cytomegalovirus pneumonia is another example of a latent infection that can
reactivate during chronic immunosuppression, especially in
solid organ and bone marrow transplant recipients. Immunosuppressive drugs used to modify inflammatory diseases, such
as tumor necrosis factor (TNF) inhibitors, have been associated
with the development of pulmonary and extrapulmonary
tuberculosis.10

MICROBIOLOGY
The microbiology of CAP and nosocomial pneumonia has been
studied extensively. Knowledge of which organisms are most
commonly associated with pneumonia in different settings is
essential because the microbial differential diagnosis guides the
diagnostic evaluation and the selection of empiric antimicrobial
therapy.
In most studies, S. pneumoniae, also called pneumococcus, is
the most commonly identified cause of CAP, accounting for
20% to 75% of cases (Table 24-3). Various other organisms have
been implicated with varying frequencies. H. influenzae, Staphylococcus aureus, and gram-negative bacilli each account for 3%
to 10% of isolates in many reports.11 Notably, the incidence of
H. influenzae pneumonia has decreased dramatically since the
introduction of the type B H. influenzae (also known as Hib)
vaccine in the 1980s. Legionella species, Chlamydophila pneumoniae, and Mycoplasma pneumoniae together account for 10%
to 20% of cases. These latter organisms, called atypical pathogens, vary in frequency in more recent reports, depending on

the age of the patient population, the season of the year, and


Pulmonary Infections  •  CHAPTER 24


TABLE 24-3 
Frequency of Pathogens in
Community-Acquired Pneumonia
Cause

Cases (%)

Streptococcus pneumoniae
Aspiration
Chlamydophila pneumoniae
Haemophilus influenzae
Gram-negative bacilli
Staphylococcus aureus
Legionella species
Viruses
Moraxella catarrhalis
Mycoplasma pneumoniae
Pneumocystis jiroveci
Mycobacterium tuberculosis
No diagnosis

20-75
6-10
4-11

3-10
3-10
3-5
2-8
2-16
1-3
1-24
0-13
0-5
25-50

geographic locale. Legionellosis and C. pneumoniae, in particular, exhibit significant geographic variation in incidence.
RULE OF THUMB
S. pneumoniae remains the most common cause of
CAP.

Many studies examining the epidemiology and microbiology
of CAP are potentially biased because they focus on patients
requiring hospitalization. In patients with less severe illnesses
not requiring hospitalization, more recent studies suggest that
M. pneumoniae and C. pneumoniae account for 38% of cases
and may be more common than typical bacterial pathogens
such as pneumococcus and H. influenzae.12 In patients who
are ill enough to require admission to the ICU, Legionella
species, gram-negative bacilli, and pneumococcus are disproportionately more common.13 A virulent strain of methicillinresistant S. aureus (MRSA) has emerged as a cause of severe
necrotizing CAP.14
In urban settings that have a high incidence of endemic HIV
infection, P. jiroveci may be an occasional cause of CAP.15 Viruses
such as influenza, respiratory syncytial virus, parainfluenza, and
adenovirus can cause CAP, especially in patients with milder

illnesses not requiring hospitalization, and are encountered in
the late fall and winter months. A worldwide pandemic of
H1N1 influenza during 2009 to 2010 and ongoing sporadic
cases of transmission of H5N1 influenza from birds to humans
have led to heightened international awareness of influenza
epidemiology, pathogenesis, and prevention.16
Mixed aerobic and anaerobic aspiration pneumonia may
account for 10% of cases. This cause of pneumonia is an important consideration for nursing home residents and for individuals with impaired gag reflexes or recent loss of consciousness.
The outbreak in 2000 to 2001 of inhalation anthrax in the
United States adds another microbial differential diagnostic

497

consideration in patients with fulminant community-acquired
LRTI.17 To date, inhalation anthrax remains a rare disease.
Several new coronaviruses have emerged as important pathogens within the past decade. Severe acute respiratory syndrome
(SARS) emerged out of Asia and spread globally in 2002 to
2003. Fortunately, no cases have been identified since 2004.18
More recently, Middle East respiratory syndrome (MERS) has
arisen as a global health concern. First described in Saudia
Arabia in 2012, the virus is found within the Arabian peninsula
and causes a severe respiratory illness with a 30% mortality rate.
The first cases imported to the United States were confirmed in
2014, both in travelers from Saudia Arabia.19 Albeit rare in the
United States, both viruses also should be considered in the
appropriate clinical and epidemiologic setting. In addition,
enterovirus D68 is an emerging cause of pneumonia in
children.20
In most published series, no microbiologic diagnosis is
established in 50% of patients. This is attributable to many

factors, including:
• Inability of many patients to produce sputum
• Acquisition of sputum specimen after antibiotics have been
started
• Failure to perform numerous serologic studies routinely in
all patients
• The fact that many organisms (e.g., viruses and anaerobic
bacteria) were not routinely sought
• Failure, until more recently, to recognize pneumonia pathogens, such as C. pneumoniae and some viral agents.
The common microbial agents producing HCAP, HAP, and
VAP are summarized in Table 24-1 and include gram-negative
bacilli, S. aureus, Legionella species, and rarely viruses such as
influenza or respiratory syncytial virus. The last-mentioned
viruses are considerations only during the winter months, when
they are endemic in the community and may enter the hospital
via health care workers, visitors, or patients with incubating or
active infections.
The relative frequencies and antimicrobial susceptibilities of
these respective bacteria may vary considerably from one institution to another. Knowledge of which nosocomial isolates are
most common within one’s own institution and community,
along with their drug-sensitivity profiles, has important implications with regard to selecting antibiotic therapy, formulating
infection control policies, investigating potential outbreaks, and
selecting antimicrobial agents for the hospital formulary. For
example, patients developing severe VAP in ICUs with a high
prevalence of carbapenem resistance among gram-negative
organisms such as Klebsiella pneumoniae and Acinetobacter baumannii may warrant empiric antimicrobial therapy for these
organisms pending culture information. Similarly, nosocomial
legionellosis occurs with variable frequency at different institutions, such that empiric therapy in critically ill patients with
nosocomial LRTI may or may not require coverage of this
pathogen.

Nosocomial pathogens capable of producing HAP can be
transmitted directly from one patient to another, as in the
case for tuberculosis. However, transmission from health care


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SECTION IV  •  Review of Cardiopulmonary Disease

workers (including respiratory therapists [RTs]), contaminated
equipment, or fomites (objects capable of transmitting infection through physical contact with them) is more common,
especially for gram-negative bacilli, S. aureus, and viruses. The
RT has an important role to play in preventing the transmission
and development of nosocomial pneumonia.

M I N I CLINI
Distinguishing Between Different Types
of Nosocomial Pneumonia
PROBLEM:  A 52-year-old man with a history of severe low

back pain is admitted to the hospital with a GI bleed in the
setting of excessive NSAID use. He has not seen a doctor in 5
years. His presenting symptoms include epigastric abdominal
pain, black stools, and dizziness with standing. Admission
hemoglobin is 5.2 g/dl and white blood count (WBC) count is
6.2 × 109. He is transfused red blood cells (RBCs) and undergoes upper GI endoscopy, which reveals a large bleeding duodenal ulcer. Three days into his admission, the patient develops
a fever to 40.2° C, shortness of breath, and cough. Laboratory
testing reveals a WBC count of 16.8 × 109. Chest radiography
reveals a patchy infiltrate in the right lower lobe. What type of
pneumonia does this patient have? How might this infection

have developed?
DISCUSSION:  The patient has HAP, because he did not have

any evidence of pneumonia at the time of admission and developed his infection more than 48 hours into his hospital stay.
He may have developed pneumonia secondary to inhalation of
infectious particles via exposure to patients or health care providers working with a respiratory illness. More likely, he aspirated oropharyngeal or gastric secretions during his upper
endoscopy procedure or during a vomiting episode. Empiric
antimicrobial coverage should target mixed aerobic and anaerobic mouth flora, S.aureus, enteric gram-negative bacilli, and
potentially influenza, depending on the season.

CLINICAL MANIFESTATIONS
Patients with CAP typically have fever and respiratory symptoms, such as cough, sputum production, pleuritic chest pain,
and dyspnea. Not all of these symptoms are present all the time,
especially in elderly patients in whom the presentation may
be subtle. Other problems, such as hoarseness, sore throat,
headache, and diarrhea, may accompany certain pathogens.
Fever, cough, and sputum production may occur in other illnesses such as acute bronchitis or exacerbations of chronic
bronchitis.
In the past, clinicians often distinguished between typical
and atypical clinical syndromes as a means of predicting the
most likely microbial causes. A typical presentation consisted of
the sudden onset of high fever, shaking, chills, and cough with
purulent sputum. Such a presentation was considered more
common with bacterial pathogens such as pneumococcus and
H. influenzae. An atypical presentation was an illness characterized by the gradual onset of fever, headache, constitutional

symptoms, diarrhea, and cough, often with minimal sputum
production. Cough was often a relatively minor symptom at
the outset, and the illness was initially dominated by nonrespiratory symptoms. Such a presentation was thought to be more
common with pathogens such as M. pneumoniae, C. pneumoniae, Legionella species, and viruses. More recent studies have

shown that considerable overlap exists in the clinical presentations of pneumonia with typical and atypical pathogens.21 The
occurrence of concomitant diarrhea, previously considered
indicative of legionellosis, is now known to be common in
pneumococcal and mycoplasmal pneumonia.
Despite the limitations in predicting the microbial diagnosis
based on the clinical presentation, clinicians use certain historical clues and physical findings at the bedside to determine the
likely cause of pneumonia in patients presenting from the community. In patients presenting with high fever, teeth-chattering
chills, pleuritic pain, and a cough producing rust-colored
sputum, pneumococcal pneumonia is the most likely diagnosis.
Patients with pneumonia accompanied by foul-smelling breath,
an absent gag reflex, or recent loss of consciousness are most
likely to have a mixed aerobic and anaerobic infection as a
consequence of aspiration. CAP accompanied by hoarseness
suggests C. pneumoniae. Pneumonia in a patient with a history
of splenectomy suggests infection with an encapsulated pathogen such as pneumococcus or H. influenzae. Pneumonia occurring after resolution of a flulike illness raises concern for
S. aureus. Epidemics of pneumonia occurring within households or closed communities, such as dormitories or military
barracks, suggest pathogens such as M. pneumoniae or C. pneumoniae. Pneumonia accompanied by splenomegaly suggests
psittacosis (caused by Chlamydophila psittaci and associated
with bird exposure) or Q fever (caused by Coxiella burnetii and
associated with exposure to farm animals). Bullous myringitis
and erythema multiforme are associated with Mycoplasma
infection. Relative bradycardia (defined as a heart rate <100
beats/min) in the presence of fever and in the absence of preexisting cardiac conduction system disease or beta-blocker
therapy may suggest infection with an atypical pathogen.
Pneumonia accompanied by conjunctivitis suggests adenovirus
infection.
The clinical presentation of CAP in elderly patients warrants
special mention because it may be subtle. Older individuals
with pneumonia may not have a fever or cough and may simply
present with shortness of breath, confusion, worsening congestive heart failure (CHF), or failure to thrive.

Inhalation anthrax is a rare disease, but warrants mention
because of the small epidemic believed to have been an act of
bioterrorism.17 This outbreak affected mainly postal workers
who were exposed to mail containing anthrax spores. Most
patients presented with a febrile flulike illness of several days’
duration accompanied by dry cough and shortness of breath.
Some patients went on to develop septic shock, meningitis, and
disseminated intravascular coagulation over several days, culminating in death.
Because of a lack of prior host immunity or unique viral
virulence factors, patients infected with pandemic influenza




Pulmonary Infections  •  CHAPTER 24

strains may have unusually severe presentations. During the
2009 to 2010 pandemic of H1N1 influenza, clinical presentations varied from mild upper respiratory syndromes to fulminant pneumonias with acute respiratory distress syndrome
(ARDS) and shock.16 SARS manifests with high fever and
myalgia for 3 to 7 days followed by nonproductive cough
and progressive hypoxemia with progression to mechanical
ventilation in 20%.18 MERS presents similarly, with an added
history of travel to or close contact with a symptomatic person
who has traveled to the Arabian peninsula within 14 days of
symptom onset.19
HCAP, HAP, and VAP usually manifest with new onset of
fever in hospitalized or institutionalized patients. Nonintubated
patients may have a recent history of vomiting, seizure, or
syncope, during which aspiration of oropharyngeal or gastric
secretions may have occurred. In intubated patients, VAP traditionally manifests with new onset of fever, leukocytosis, purulent endotracheal secretions, and a new pulmonary infiltrate.

The diagnosis of HCAP, HAP, or VAP can be extremely difficult
to make in patients with preexisting abnormalities on the chest
radiograph, such as CHF or ARDS. In mechanically ventilated
patients, purulent tracheobronchitis may be accompanied by
fever, and in patients with preexisting abnormalities on chest
radiograph, the distinction between bronchitis and pneumonia
can be especially difficult.

TABLE 24-4 

499

Radiographic Patterns Produced by Pathogens in
Community-Acquired Pneumonia
Pattern

Pathogens

Lobar consolidation
Bronchopneumonia
Pleural effusion

Bacterial
Bacterial
Bacterial
Inhalation anthrax
Viruses
Pneumocytis jiroveci
Mycobacteria
Fungi

Nocardia species
Staphylococcus aureus
Gram-negative bacilli
Polymicrobial aerobic and
anaerobic lung abscess
P. jiroveci (rare)
Inhalation anthrax

Interstitial infiltrates
Cavities

Mediastinal widening without
infiltrates
Rapidly progressive multilobar

Legionella species
Streptococcus pneumoniae
Endobronchial tuberculosis

CHEST RADIOGRAPH
In patients with a compatible clinical syndrome, the diagnosis
of CAP is established by the presence of a new pulmonary
infiltrate on the chest radiograph. Not all healthy outpatients
with suspected pneumonia require a chest radiograph, and physicians may choose not to obtain a chest radiograph and treat
empirically for CAP in individuals with mild illnesses who are
at low risk for morbidity or mortality.
Also, a normal chest radiograph does not exclude the diagnosis of pneumonia. The chest radiograph may be normal
in patients with early infection, dehydration, or P. jiroveci
infection. The pattern of radiographic abnormality is not diagnostic of the causative agent, although specific radiographic
findings should suggest specific microbial differential diagnoses

(Table 24-4).
Consolidation involving an entire lobe is called lobar consolidation (Figure 24-1), whereas bronchopneumonia refers to the
presence of a patchy infiltrate surrounding one or more bronchi,
without opacification of an entire lobe. Both radiographic patterns suggest the presence of a bacterial pathogen. Pleural effusions are common in patients with bacterial pneumonia and
uncommon in patients with viral, P. jiroveci, C. pneumoniae, or
fungal pneumonia. Pleural effusions are seen in approximately
10% of patients with M. pneumoniae and Legionella pneumophila pneumonia and occur occasionally in patients with reactivation pulmonary tuberculosis. Interstitial infiltrates (Figure
24-2), especially if diffuse, suggest viral disease, P. jiroveci, or
miliary tuberculosis in patients with CAP. Cavitary infiltrates
(Figure 24-3) are seen in reactivation pulmonary tuberculosis;

FIGURE 24-1  Lobar pneumonia caused by Streptococcus
pneumoniae. A 36-year-old previously healthy woman presents
with abrupt onset of fevers and shaking chills, cough productive
of yellow sputum, and right-sided pleuritic chest pain. Chest
radiograph reveals lobar consolidation. Sputum culture yields
S. pneumoniae.

fungal pneumonias, such as histoplasmosis, blastomycosis, and
aspergilosis; nocardiosis; pyogenic lung abscess; and, rarely,
P. jiroveci pneumonia. Patients with severe staphylococcal or
gram-negative pneumonias may develop small cavities called
pneumatoceles. Legionellosis should be considered in sicker


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SECTION IV  •  Review of Cardiopulmonary Disease
patients with pneumonia of a single lobe, which quickly spreads
to involve multiple lobes over 24 to 48 hours.

The chest radiograph may be helpful in diagnosing HCAP
or HAP in nonintubated patients with a suspected aspiration
event and a prevously normal chest film. In such cases, development of a new infiltrate may confirm the clinical suspicion of
aspiration pneumonia. The chest radiograph is often less helpful
in the diagnosis of VAP because mechanically ventilated patients
often have other reasons for radiographic abnormalities, such
as ARDS, CHF, pulmonary thromboembolism, alveolar hemorrhage, or atelectasis. In these patients, the accurate diagnosis of
a new nosocomial LRTI can be difficult. Clinical diagnosis,
defined as the presence of fever, purulent respiratory secretions,
new leukocytosis, and a new pulmonary infiltrate, is sensitive
but not specific for the diagnosis of VAP. Other strategies to
diagnose VAP more accurately have been investigated.

RISK FACTORS FOR MORTALITY
AND ASSESSING THE NEED
FOR HOSPITALIZATION
FIGURE 24-2  Pneumocystis jiorveci pneumonia (PCP). A
23-year-old male intravenous drug user presents with 2 weeks of
dyspnea on exertion, nonproductive cough, and fevers to 40.4° C.
The chest radiograph shows an interstitial infiltrate. Human
immunodeficiency virus antibody test is positive, serum beta-D
glucan level is elevated, and bronchoalveolar lavage toluidine blue O
stain is positive for P. jiroveci. The interstitial infiltrate in a “bat-wing”
distribution is classic for PCP pneumonia.

FIGURE 24-3  Cavitary nodular pneumonia caused by
Aspergillus. A 34-year-old woman undergoing induction
chemotherapy for newly diagnosed acute myeloid leukemia
presents with persistent neutropenic fevers and cough productive
of scant hemoptysis. Sputum cultures are negative, but serum

galactomannan antigen is markedly elevated, highly suggestive of
Aspergillus infection. Computed tomography reveals multicentric
cavitary nodules, some of which have a halo of ground glass
opacity surrounding them, findings that are classic for invasive
pulmonary aspergillosis.

Many cases of CAP can be managed successfully on an outpatient basis. The challenge for the clinician is to identify individuals at higher risk of morbidity and mortality for whom
hospitalization is indicated. Over the past 20 years, numerous
studies have analyzed risk factors for mortality in patients with
CAP.21-23 Risk factors predicting a high risk for death are summarized in Box 24-1.
Fine and associates23 performed a meta-analysis of 127
cohorts of patients with CAP to examine risk factors for death.
The overall mortality for the 33,148 patients in these cohorts
was 13.7%. Eleven prognostic variables were significantly associated with mortality, including male sex, absence of pleuritic
chest pain, hypothermia, systolic hypotension, tachypnea, diabetes mellitus, cancer, neurologic disease, bacteremia, leukopenia, and multilobar infiltrates on chest radiograph. Mortality
varied according to the infecting agent and was highest for P.
aeruginosa (61.1%), Klebsiella species (35.7%), Escherichia coli
(35.3%), and S. aureus (31.8%). Mortality rates for more
common pathogens were lower but still substantial: Legionella
species (14.7%), S. pneumoniae (12.3%), C. pneumoniae (9.8%),
and M. pneumoniae (1.4%).
Because some variables are unknown at the time a patient
seeks treatment for pneumonia, such as the causative agent and
whether bacteremia is present, more recent studies have sought
to assess the risk for fatal outcome by using clinical and laboratory data that are readily available at the time of the initial
evaluation. Based on an analysis of the 30-day mortality in
more than 40,000 patients, Fine and associates24 proposed a
prediction rule to identify low-risk and high-risk patients with
CAP. Their algorithm uses the demographic, clinical, and laboratory data available at presentation to stratify the risk for
death and the criteria for hospitalization in outpatient groups.

Points are assigned for the presence of numerous variables, and
cumulative point scores are used to stratify patients into one
of five different risk groups with predictable mortality rates


Pulmonary Infections  •  CHAPTER 24


Box 24-1

Risk Factors for Mortality in
Community-Acquired Pneumonia
from Multiple Studies

I. Patient variables
A. Age >50 years
B. Male sex
C. Comorbid illnesses
1. Cerebrovascular disease
2. Cancer
3. Congestive heart failure
4. Renal disease
5. Liver disease
6. Immunosuppression
7. Alcoholism
8. Diabetes mellitus
9. Chronic lung disease
II. Clinical parameters at presentation
A. Altered mentation
B. Systolic hypotension <90 mm Hg

C. Tachypnea >30 breaths/min
D. Hypothermia (temperature <35° C)
E. Fever (temperature >40° C)
F. Pulse rate >125 beats/min
G. Extrapulmonary site of infection
III. Laboratory and radiographic findings at presentation
A. Arterial pH <7.35
B. Blood urea nitrogen >30 mg/dl
C. Serum sodium <130 mmol/L
D. Glucose >250 mg/dl
E. Hematocrit <30%
F. Hypoxia (PaO2 <60 mm Hg) or hypercarbia (PCO2 >
50 mm Hg) on room air
G. White blood cell count <4 × 109/L, >30 × 109/L, or an
absolute neutrophil count <1 × 109
H. Multilobar infiltrate
I. Bacteremia
J. Pleural effusion
K. High-risk cause
1. Gram-negative bacilli
2. Staphylococcus aureus
3. Postobstructive pneumonia
4. Aspiration
From Fine MJ, Smith MA, Carson CA, et al: Prognosis and outcomes of
patients with community-acquired pneumonia: a meta-analysis. JAMA
275:134–141, 1996.

(Tables 24-5 and 24-6). In this model, which has been validated
in large prospective cohorts of patients, the patients at the
lowest risk for death fall into groups I and II. In most instances,

these patients may be treated successfully as outpatients, unless
they are hypoxemic, vomiting and unable to take oral antibiotics, noncompliant, or immunocompromised. Patients in group
I are patients younger than 50 years of age without comorbid
illnesses and abnormal physical findings at presentation (see
Box 24-1 and Table 24-5). This group of patients has a 0.1%
risk for death.
Because of the complexity of the pneumonia severity index,
many practitioners prefer a simpler stratification system,
CURB-65. Risk criteria in this system include confusion, blood
urea nitrogen greater than 20 mg/dl, respiratory rate greater

501

TABLE 24-5 
Scoring System for Stratifying Risk of
30-Day Mortality in Adults With
Community-Acquired Pneumonia
Variable
Age
  Men
  Women
Nursing home resident
Comorbid illnesses
  Cancer
  Liver disease
  Kidney disease
  Cerebrovascular disease
  Congestive heart failure
Physical findings
  Altered mentation

  Tachypnea >30 breaths/min
  Systolic hypotension <90 mm Hg
  Temperature <35° C or >40° C
  Heart rate >125 beats/min
Laboratory and radiographic findings
  Acidemia (arterial pH <7.35)
  Azotemia (blood urea nitrogen >30 mg/dl)
  Hyponatremia (sodium <130 mmol/L)
  Hypoxia (PaO2 <60 mm Hg)
  Hyperglycemia (glucose >250 mg/dl)
  Anemia (hematocrit <30%)
  Pleural effusion

Points Assigned
Age (yr)
Age (yr) − 10
+10
+30
+20
+10
+10
+10
+20
+20
+20
+15
+10
+30
+20
+20

+10
+10
+10
+10

Modified from Fine MJ, Auble TE, Yealy DM, et al: A prediction rule to
identify low-risk patients with community-acquired pneumonia. N Engl J Med
336:243–250, 1997.
NOTE: Plus sign (+) denotes adding points; minus sign (−) denotes subtracting
points (e.g., for women, points assigned equal age in years − 10).

TABLE 24-6 
Risk Class Mortality Rates Using Prediction Model
Cumulative Point Scores in Patients With
Community-Acquired Pneumonia
Risk Class (Cumulative Point Score)
I
II (≤70)
III (71-90)
IV (91-130)
V (>130)

Mortality Rate (%)
0.1
0.6
2.8
8.2
29.2

Modified from Fine MJ, Auble TE, Yealy DM, et al: A prediction rule to

identify low-risk patients with community-acquired pneumonia. N Engl J Med
336:243–250, 1997.
NOTE: Patients in risk class I are <50 years old and lack existing illness or
physical findings listed in Table 19-5. Points are assigned to patients in risk
classes II and higher.

than 30 breaths/min, systolic blood pressure less than 90 mm Hg
or diastolic blood pressure less than 60 mm Hg, and age older
than 65 years. Based on their data analysis, the authors recommend that patients with one or two risk criteria should be
treated as outpatients, patients with two criteria treated on
general hospital wards, and patients with three or more criteria
admitted to the ICU.25


502

SECTION IV  •  Review of Cardiopulmonary Disease

Many studies have examined risk factors for the development of HAP and VAP, which in broad terms can be divided
into (1) factors that interfere with host defense and (2) factors
that encourage exposure to large numbers of bacteria.7 Examples of factors that interfere with host defense include the
following:
• Underlying illnesses such as diabetes mellitus, malignancy,
chronic heart and lung disease, and renal failure
• Critical illnesses such as sepsis syndrome and ARDS
• Therapeutic interventions such as endotracheal intubation,
tracheostomy, and administration of medications such as
sedatives and corticosteroids
Factors that promote exposure of the lung to pathogenic
microorganisms include the following:

• Use of endotracheal or nasogastric tubes
• Contaminated ventilator equipment or water supplies
• Prior antibiotic therapy
• Neutralization of gastric pH
Although many studies have emphasized the substantial
mortality rate (20% to 50%) for patients who develop HAP or
VAP, few studies have examined the specific risk factors associated with mortality in hospital-acquired LRTI. For nonventilated patients, risk factors for mortality include bilateral
infiltrates, respiratory failure, and infection with high-risk
organisms.26,27 In mechanically ventilated patients, factors associated with fatal outcome include the following27,28:
• Infection with high-risk organisms such as P. aeruginosa,
Acinetobacter species, and Stenotrophomonas maltophilia
• Multisystem organ failure
• Nonsurgical diagnosis
• Therapy with antacids or histamine-2 (H2)-receptor
antagonists
• Transfer from another hospital or ward
• Renal failure
• Prolonged mechanical ventilation
• Coma or shock
• Inappropriate antibiotic therapy
• Hospitalization in a noncardiac ICU
Her cumulative point score is 225, she belongs in risk class
V, and her estimated risk for mortality is 29.2% (see Table 24-6).
She should be admitted to the hospital for treatment.

DIAGNOSTIC STUDIES

MINI CLINI
Estimating Risk from Pneumonia
PROBLEM:  The RT is called to the emergency department to

perform an arterial blood gas analysis on a 70-year-old woman
who has been sent from a nursing home with confusion and
shortness of breath. Her history is notable for end-stage renal
disease caused by hypertension and a recent stroke, which has
resulted in left-sided hemiplegia. The emergency physician
ordered a chest x-ray examination, which revealed a right lower
lobe infiltrate and a right pleural effusion.
On physical examination, the patient is somnolent. Her vital
signs are temperature, 35° C; blood pressure, 85/50 mm Hg;
and heart rate, 130 beats/min. Additional findings include the
following:
• Absent gag reflex
• Right basilar rales (crackles) and left hemiplegia
3
• Peripheral white blood cell (WBC) count, 3000 cells/mm
• Blood urea nitrogen, 100 mg/dl
• Hematocrit, 31%
• Blood glucose, 110 mg/dl
• Serum sodium, 144 mmol/L
The RT collects the arterial blood gas on room air, which
shows a pH of 7.30; PaO2, 58 mm Hg; and PCO2, 25 mm Hg.
Should the patient be admitted to the hospital, or should she
be sent back to the nursing home? What is her risk for 30-day
mortality?
DISCUSSION:  This patient is at substantial risk for dying

from pneumonia and should be admitted to the hospital. The
Fine prediction rule24 may be used as follows to estimate the
risk for 30-day mortality (see Tables 24-5 and 24-6):

Variable
Age 70 yr
Sex female
Nursing home resident
Cerebrovascular disease
Renal disease
Altered mentation
Systolic hypotension
Hypothermia
Tachycardia
Acidemia
Renal failure
Hypoxemia, with PaO2 <60 mm Hg
Pleural effusion
Total

Points
+70
−10
+10
+10
+10
+20
+20
+15
+10
+30
+20
+10
+10

225

Community-Acquired Pneumonia
Many patients with CAP who are treated as outpatients never
have a microbiologic diagnosis established. Many are treated
based on the history and examination findings, with or without
a chest radiograph to confirm the presence of an infiltrate.
Patients who are sick enough to warrant hospitalization or
consideration of hospitalization should undergo appropriate
studies to stratify risk for mortality and establish a microbiologic diagnosis (Box 24-2). Complete blood count, blood
glucose, serum sodium, and blood urea nitrogen are all necessary to derive a point score for estimating mortality risk. An

arterial blood gas analysis is used to detect the presence of
hypoxemia and acidemia, which indicate more serious illness.
The value of Gram stain and culture of expectorated sputum
has been debated for years.29 Many patients lack a productive
cough, making collection of an adequate specimen difficult.
Prior antibiotic therapy reduces the yield from both tests. Only
50% of patients with bacteremic pneumococcal pneumonia
have a positive sputum culture.30 Nevertheless, the finding of a
predominant organism on Gram stain in an appropriately collected specimen can be very helpful in selecting appropriate


Pulmonary Infections  •  CHAPTER 24


Box 24-2

•
•

•

•
•
•

•
•

•

Recommended Tests for Adults
With Community-Acquired
Pneumonia Warranting
Consideration of Hospitalization

Chest radiograph
Complete blood count
Blood chemistries
• Glucose
• Serum sodium
• Blood urea nitrogen
Arterial blood gas
Sputum Gram stain and culture
Additional sputum studies as clinically indicated
• Acid-fast stains and culture for mycobacteria
• Potassium hydroxide examination and fungal culture
• Stain for Pneumocystis jiroveci
• Direct fluorescent antibody stain for Legionella species
Blood cultures

Pleural fluid analysis if sizable effusion is present
• Cell count with differential
• Glucose, protein, and lactate dehydrogenase
• pH
• Gram stain and routine aerobic and anaerobic culture
• Acid-fast stain and culture for mycobacteria
Additional other studies as clinically indicated
• Legionella urinary antigen
• Pneumococcal urinary antigen
• Acute and convalescent sera for Mycoplasma
pneumoniae, Legionella species, and Chlamydophila
pneumoniae
• Fungal serologies
• HIV test for individuals 15 to 65 years old or for
individuals engaging in high-risk behavior

antibiotic therapy.31 A routine sputum culture must be interpreted within the context of the sputum Gram stain. Specimens
contaminated with oropharyngeal epithelial cells are unsatisfactory for analysis and specimens lacking neutrophils from nonneutropenic patients are unlikely to be helpful.
RULE OF THUMB
A routine sputum culture can be interpreted only within
the context of the sputum Gram stain.

The RT has an important role in collecting an appropriate
specimen of expectorated sputum. Patients should be advised
to rid the mouth of contaminating saliva by rinsing with water
or by spitting and then to expectorate a specimen from deep
within the tracheobronchial tree into a collection container.
Prompt transportation to the laboratory is essential and
improves the diagnostic yield from culture.12 Most microbiology laboratories screen the adequacy of the specimen by cytologic examination. A satisfactory specimen contains more than
25 leukocytes and fewer than 10 squamous epithelial cells per

high-power field.32 In routine sputum culture, the isolation of
bacteria such as S. pneumoniae and H. influenzae must be interpreted within the context of the Gram stain because these

503

organisms can colonize the oropharynx, and their presence in
culture may not signify true LRTI. The culture isolation of other
organisms, such as Mycobacterium tuberculosis, Histoplasma
capsulatum, Blastomyces dermatitidis, Coccidioides immitis, and
Legionella species is diagnostic of disease because these organisms almost never colonize the respiratory tract.
RULE OF THUMB
The presence of Candida species on sputum smear or
culture is almost never clinically significant.

Other stains and cultures of expectorated sputum should be
obtained as dictated by the clinical circumstance, when management would be changed, or for purposes of tracking unusual
or resistant organisms in an institution or population. In
patients with suspected tuberculosis, the finding of acid-fact
bacilli in stained sputum specimens often prompts initiation of
antituberculous therapy because culture isolation of M. tuberculosis may take 6 weeks. A direct fluorescence antibody stain
of sputum for Legionella species may reveal the organism in
25% to 80% of individuals with Legionnaire’s disease, and cultures are positive in 50% to 70%.33 Toluidine blue O stains
of sputum may disclose the organism in 80% of patients with
P. jiroveci pneumonia. Potassium hydroxide preparations of
sputum show fungi in only a few patients with histoplasmosis,
blastomycosis, or coccidioidomycosis but are very helpful if
positive.
Blood cultures should be obtained in hospitalized patients
with CAP and may be helpful in establishing the diagnosis in
patients with typical bacterial pathogens. Blood cultures are

positive in approximately 30% of patients with pneumococcal
pneumonia and in 70% of patients with H. influenzae pneu­
monia.34 Blood cultures are not helpful in patients with legionellosis, M. pneumoniae, C. pneumoniae, P. jiroveci, or viral
infections. Collection of blood cultures within 24 hours of hospitalization in elderly patients with pneumonia has been associated with improved survival.35
Parapneumonic pleural effusions are common and occur in
30% to 50% of patients with CAP.11 Thoracentesis is indicated
for patients with large pleural effusions and patients with
smaller effusions who fail to respond to therapy or for whom
the microbiologic diagnosis is not established. Pleural fluid
should be tested for cell count, glucose, protein, pH, lactate
dehydrogenase, Gram and acid-fast bacilli stains, and routine
(aerobic and anaerobic) and mycobacterial cultures. Effusions
with a fluid pH less than 7.20, a positive Gram stain or culture,
or fluid that appear grossly purulent on inspection require tube
thoracostomy for drainage.36
Other studies may be helpful in establishing a microbiologic
diagnosis in the appropriate clinical setting. L. pneumophila
serogroup 1 accounts for 80% of cases of Legionnaire’s disease.37
The urinary antigen test for L. pneumophila serogroup 1 is a
sensitive and rapid test and usually becomes positive within 3
days of illness onset, but the test has limitations. First is its


504

SECTION IV  •  Review of Cardiopulmonary Disease

inability to detect the non–serogroup 1 L. pneumophila and
non–L. pneumophila species that account for 20% of cases of
Legionnaire’s disease. Second, it can be negative if patients

present very early in the disease course, potentially misleading
clinicians with a negative result and requiring repeat testing if
clinical suspicion remains high. Third, the test may remain
positive for 1 year, obviating the ability to distinguish new
from remote infection in patients with a recent history of
pneumonia.
Serologic tests for immunoglobulin M (IgM) and IgG antibodies to M. pneumoniae, Legionella species, or C. pneumoniae
are rarely helpful during the initial stages of pneumonia, but
convalescent titers 3 to 4 weeks later may permit a retrospective
microbiologic diagnosis by showing a fourfold increase in IgG
titer or the development of IgM antibody against a specific
pathogen. Acute sera should be analyzed in patients who are
critically ill with pneumonia and for whom the microbiologic
diagnosis is unavailable. Fungal serologic findings are occasionally helpful in supporting the diagnosis of blastomycosis, histoplasmosis, or coccidioidomycosis, pending culture isolation of
the organism.
Fungal antigen assays are increasingly being used in settings
in which there is a high clinical suspicion for invasive fungal
infection. Invasive aspergillosis is is an important cause of
pneumonia in immunocompromised hosts, particularly in
those with prolonged neutropenia. Galactomannan is a polysaccharide that is a major constituent of Aspergillus cell walls. A
large meta-analysis revealed that galactomannan antigen assays
have a sensitivity of 71% and specificity of 89% for Aspergillus
infection.38 However, the sensitivity of the test is decreased by
concomitant administration of antifungal therapy and falsepositive results can occur in patients receiving the antibiotic
combination piperacillin-tazobactam in infections with other
fungi that share cross-reacting antigens (Fusarium and Penicillium species, H. capsulatum) and in patients with chemotherapyinduced mucositis or transplant-associated graft-versus-host
disease (in whom bacteria with cross-reactive antigens translocate across the intestinal mucosal wall). Similarly, 1,3-beta-Dglucan is a cell wall component of many fungi, and levels of this
molecule are elevated in many types of invasive fungal infection, including those with Aspergillus, P. jiroveci, H. capsulatum,
and C. immitis. Beta-D glucan assays have a sensitivity of 77%
and specificity of 85% for invasive fungal infection.39 Like the

galactomannan assay, there are some drawbacks to this test.
First, the assay cannot distinguish between infections from
various fungal pathogens. False-positive results can occur in
patients receiving intravenous immunoglobulin or albumin
infusions, in patients undergoing hemodialysis or receiving
intravenous infusions that use cellulose filters, in patients with
glucan-containing gauze packing of serosal surfaces, and
patients who are bacteremic with certain organisms, including
Pseudomonas aeruginosa.39
Because pneumococcal and H. influenzae pneumonia occur
with higher frequency in patients with HIV infection than in
the average population, an HIV test is recommended for patients
ages 15 to 65 with CAP. HIV testing is also recommended for

other individuals who engage in behaviors that put them at risk
for HIV infection.
Molecular techniques, such as DNA probes and polymerase
chain reaction (PCR), used for detecting specific organisms
such as M. pneumoniae or M. tuberculosis or for confirming the
identity of culture isolates, are being developed and used in
some larger centers. Rapid diagnostic testing of nasopharyngeal
specimens for viral pathogens such as influenza, parainfluenza,
and respiratory syncytial virus may be helpful in diagnosing
CAP because of these organisms in patients with compatible
clinical presentations.

MINI CLINI
Importance of Clinical Setting for
Determining the Cause of Pneumonia
PROBLEM:  The RT is caring for a 32-year-old man admitted

to the hospital 24 hours earlier with fever, shaking chills, and a
new left lower lobe infiltrate. His WBC count on admission was
3500 cells/mm3, with 96% neutrophils and 4% lymphocytes. A
sputum Gram stain disclosed many polymorphonuclear leukocytes and lancet-shaped, gram-positive diplococci. Blood cultures have grown S. pneumoniae at 24 hours. He remains febrile
24 hours into therapy with penicillin G. While checking pulse
oximetry, the RT notes that the patient is emaciated and that
multiple needle tracks are present in each antecubital fossa. He
tells the RT that he uses intravenous heroin. What other tests
are indicated?
DISCUSSION:  This patient, who is an intravenous drug user,

has bacteremic pneumococcal pneumonia. These findings,
along with the presence of cachexia and leukopenia with lymphopenia, should suggest the possibility of underlying HIV
infection. An HIV test is indicated and should be performed
after the patient’s consent is obtained.
Both pneumococcal and H. influenzae pneumonia occur
with higher frequency in HIV-infected individuals than in the
general population. Occasionally, an HIV-infected patient has
his or her first contact with the health care system as a result
of one of these infections. New guidelines recommend that all
average-risk individuals ages 15 to 65 undergo testing for HIV
once in their lives and persons at higher risk for HIV infection
undergo more frequent testing.40

Flexible bronchoscopy is usually reserved for severe cases of
CAP, for immunocompromised individuals in whom opportunistic pathogens must be excluded, or for cases in which P. jiroveci infection is suspected. The yield from flexible bronchoscopy
is higher if performed before starting antibiotic therapy in
patients with bacterial pneumonia. Open lung biopsy is rarely
indicated for patients with CAP.

Health Care–Associated Pneumonia,
Hospital-Acquired Pneumonia, and
Ventilator-Associated Pneumonia
The accurate diagnosis of nosocomial pneumonia is challenging and has been the subject of intense investigation over the


Pulmonary Infections  •  CHAPTER 24


Box 24-3

Techniques for Diagnosing
Nosocomial Pneumonia

•
•
•

Clinical diagnosis
Direct visualization of the airway by bronchoscopy
Quantitative cultures of:
• Endotracheal aspirates
• Protected brush–bronchoscopy specimens
• Nonbronchoscopic distally protected specimens
• Conventional or protected BAL specimens, plus
microscopic examination of recovered cells
• PSB and BAL specimens, plus microscopic examination
of BAL fluid cells
• RT-directed mini-BAL

• Transthoracic fine-needle aspiration
BAL, Bronchoalveolar lavage; PSB, protected specimen brush; RT,
respiratory therapist.

past three decades. Numerous techniques have been extensively
evaluated (Box 24-3); however, none is absolutely sensitive and
specific.41,42 Clinical diagnosis has been defined as the development of a new infiltrate on chest radiograph in the setting of
fever, purulent tracheal secretions, and leukocytosis in a hospitalized patient. Clinical diagnosis lacks specificity because many
other causes of pulmonary infiltrates exist in hospitalized
patients, especially in patients on mechanical ventilation.43 In
addition, the upper airway commonly is colonized with nosocomial gram-negative bacilli and staphylococci, even in the
absence of pneumonia. The qualitative culture isolation of these
organisms from tracheal secretions correlates poorly with the
presence or absence of pneumonia.
Direct visualization of the lower airway by bronchoscopy in
ventilated patients is sometimes helpful to support the diagnosis of VAP. In one study, the presence of distal, purulent secretions, persistence of secretions surging from distal bronchi
during exhalation, and a decrease in the PaO2/FiO2 ratio of less
than 50 were independently associated with the presence of
pneumonia. The presence of two of three of these factors had
a sensitivity of 78% in the diagnosing nosocomial pneumonia;
these factors were absent 89% of the time when there was no
pneumonia (89% specific).44
Because the specificity of qualitative sputum cultures has
been unreliable, several studies have examined the role of quantitative cultures of endotracheal aspirates using various breakpoints ranging from 103 to 107 colony-forming units (CFUs) per
milliliter of respiratory secretions. Results with this technique
have been best using a breakpoint of 106 CFU/ml, but sensitivities have been only 68% to 82%, with specificities of 84% to
96% with this test.45,46
The protected specimen brush (PSB) was developed in the
1970s and uses a special double-catheter brush system to minimize contamination by upper airway flora. Specimens obtained
with this technique are cultured quantitatively. Numerous

studies have validated the sensitivity of PSB in diagnosing nosocomial pneumonia.47,48 However, PSB may be less useful in cases
in which antibiotics have already been started, in cases of early
infection, and in cases in which the wrong lobe is sampled.41

505

Nonbronchoscopic techniques using telescoping protected
catheters have also been developed to obtain specimens for
quantitative culture from the lower airway. In most studies,
sensitivity has been comparable to bronchoscopic techniques,
but results have disagreed in 20% of cases.41
Bronchoalveolar lavage (BAL), in which a lung segment is
lavaged with sterile saline through the bronchoscope and recovered fluid is quantitatively cultured, has been studied extensively as a tool for diagnosing nosocomial pneumonia (see
Chapter 24). Some studies have supported the usefulness of this
technique, and others have questioned its specificity because of
upper airway contamination.47,48 BAL has proved useful for
obtaining alveolar cells for microscopic analysis; several studies
have suggested that the presence of intracellular bacteria in 3%
to 5% of BAL cells distinguishes patients with nosocomial
pneumonia from patients without pneumonia.47,48 In one study,
the combination of PSB cultures and microscopic examination
of BAL cells for intracellular bacteria was 100% sensitive
and 96% specific in identifying patients with nosocomial
pneumonia.47
Mini-BAL performed by RTs also has been advocated for
diagnosing VAP. In one study, results obtained using this technique were comparable with results obtained by bronchoscopy
using PSB.49 Some centers use this technique as the primary
method of sampling respiratory secretions in suspected nosocomial pneumonia. Transthoracic ultrathin needle aspiration of
the lung in nonventilated patients with nosocomial pneumonia
also has been studied and in one report was found to have a

sensitivity of 60%, a specificity of 100%, and a positive predictive value of 100%.50
Accurately diagnosing HAP, HCAP, and VAP remains a challenge for the physician and the RT. None of the available diagnostic techniques is 100% sensitive or specific; all are limited
in the populations at greatest risk for getting nosocomial
pneumonia—mechanically ventilated patients and patients
receiving prior antibiotic therapy.

ANTIBIOTIC THERAPY
Community-Acquired Pneumonia
The selection of antibiotic therapy for patients with CAP should
be guided by several considerations, including the age of the
patient, severity of the illness, presence of risk factors for
specific organisms, and results of initial diagnostic studies.
Pathogen-specific therapy should be used when clinical circumstances and initial evaluation strongly suggest the microbiologic
diagnosis or when cultures or other studies confirm the cause.
In many instances, initial studies fail to establish a diagnosis,
and empiric therapy must be started. Major classes of antibiotics used to treat pneumonia are listed in Table 24-7. Consensus
guidelines for therapy have been published by the American
Thoracic Society (ATS) and the Infectious Diseases Society of
America (IDSA) (Table 24-8).51-53 Therapy initiated within 4
hours of hospital admission has been associated with improved
survival.35


506

SECTION IV  •  Review of Cardiopulmonary Disease

For hospitalized patients who are not critically ill and who
are admitted to the ward, an empiric regimen of a respiratory
fluoroquinolone alone or an advanced macrolide plus a betalactam (cefotaxime, ceftriaxone, or ampicillin) is recommended

(see Table 24-8). For critically ill patients requiring admission
to the ICU, the IDSA and ATS recommend as empiric therapy
a beta-lactam (cefotaxime, ceftriaxone, or ampicillin-sulbactam)
plus either an advanced macrolide or a respiratory fluoroquinolone for legionella coverage. Certain pathogens require
specific consideration in the ICU setting. If Pseudomonas is
a concern, recommended regimens include two drugs with

TABLE 24-7 
Major Classes of Antibiotics Used in
the Treatment of Pneumonia
Antibiotic Class

Representative Drugs

Penicillins
Ureidopenicillins
Semisynthetic penicillins
First-generation
cephalosporins
Second-generation
cephalosporins
Third-generation
cephalosporins
Antipseudomonal
cephalosporins
Carbapenems
Monobactams
Beta-lactam/beta-lactamase
inhibitor combinations
Quinolones

Penicillin G, ampicillin
Ticarcillin, piperacillin, mezlocillin
Oxacillin, nafcillin
Cefazolin

Macrolides
Tetracyclines
Glycopeptides
Oxazolidinones

Cefuroxime
Cefotaxime, ceftriaxone,
ceftizoxime
Ceftazidime, cefepime
Imipenem, meropenem, ertapenem
Aztreonam
Ticarcillin/clavulanate, piperacillin/
tazobactam, ampicillin/sulbactam
Ciprofloxacin, levofloxacin,
moxifloxacin, gemifloxacin
Erythromycin, clarithromycin,
azithromycin
Doxycycline
Vancomycin
Linezolid

antipseudomonal coverage: an antipseudomonal beta-lactam
(piperacillin-tazobactam, cefepime, imipenem, or meropenem)
and ciprofloxacin or levofloxacin; an antipseudomonal betalactam, an aminoglycoside, and azithromycin; or an antipseudomonal beta-lactam, an aminoglycoside, and a respiratory

fluoroquinolone (see Table 24-8). When MRSA is a concern,
addition of vancomycin or linezolid is recommended.
When a microbiologic diagnosis is established, the antimicrobial regimen should be tailored to the isolated pathogen.
Pathogen-specific treatment recommendations from the IDSA
and ATS are summarized in Table 24-9. For isolates of S. pneumoniae susceptible to penicillin, penicillin remains the preferred
agent. Many strains of H. influenzae produce beta-lactamase,
making them resistant to penicillin. Second- or third-generation
cephalosporins and amoxicillin/clavulanate are the agents of
choice. Legionellosis should be treated with a macrolide or with
a fluoroquinolone alone. Pneumonia caused by M. pneumoniae
and C. pneumoniae should be treated with a macrolide or doxycycline. Trimethoprim-sulfamethoxazole (TMP-SMX) is the
drug of choice for P. jiroveci pneumonia. However, 50% of HIVinfected patients may develop fever or a rash while taking this
medication. For patients with mild to moderate disease, atovaquone, clindamycin, and primaquine, or trimethoprim and
dapsone, are treatment alternatives; pentamidine is indicated
for severe infection in patients unable to tolerate TMP-SMX.
Treatment for staphylococcal or gram-negative pneumonias is
dictated by the antibiotic susceptibility profiles of the offending
organism. For patients with staphylococcal pneumonia, vancomycin is preferred, pending antibiotic susceptibility results. If
the isolate is methicillin-susceptible, a semisynthetic penicillin,
such as oxacillin or nafcillin, should be used because these antibiotics kill the bacteria more effectively than vancomycin; in
seriously ill patients, rifampin or an aminoglycoside may be
added. A detailed discussion regarding the treatment of fungal
and viral pneumonias is beyond the scope of this chapter.
The duration of therapy of CAP is guided by the specific
pathogen and the patient’s clinical course. Recommendations

TABLE 24-8 
Empiric Regimens for Treatment of Hospitalized Adults With Community-Acquired Pneumonia
Patient Group

Likely Pathogens

Empiric Regimens

Hospitalized on
ward

Streptococcus pneumoniae, Haemophilus influenzae,
Chlamydophila pneumoniae, Staphylococcus aureus,
Mycoplasma pneumoniae, anaerobes, viruses
S. pneumoniae, Legionella species, S. aureus,
gram-negative bacilli, M. pneumoniae, C.
pneumoniae

Respiratory fluoroquinolone (levofloxacin, moxifloxacin,
gemifloxacin) alone or beta-lactam (cefotaxime, ceftriaxone,
ampicillin, ertapenem) and macrolide
If Pseudomonas aeruginosa unlikely: Beta-lactam (cefotaxime,
ceftriaxone, ampicillin-sulbactam) plus either azithromycin or
a respiratory fluoroquinolone
If P. aeruginosa possible: IV antipseudomonal beta-lactam
(piperacillin-tazobactam, cefepime, imipenem, meropenem)
plus fluoroquinolone (ciprofloxacin or levofloxacin) or IV
antipseudomonal beta-lactam plus aminoglycoside plus
either IV macrolide or fluoroquinolone

Critically ill, ICU

Modified from Mandell MA, Wunderink RG, Anzueto A, et al: Infectious Disease Society of America/American Thoracic Society consensus guidelines on the
management of community-acquired pneumonia in adults. Clin Infect Dis 44:S27–S72, 2007.

IV, Intravenous; PO, by mouth.


Pulmonary Infections  •  CHAPTER 24


TABLE 24-9 
Pathogen-Specific Treatment Recommendations
for Adults With Community-Acquired Pneumonia:
Infectious Disease Society of America Guidelines
Pathogen
Streptococcus pneumoniae
  Penicillin susceptible
  Penicillin resistant
Haemophilus influenzae
Legionella species
Mycoplasma pneumoniae
Chlamydophila pneumoniae
Staphylococcus aureus
Methicillin susceptible
Methicillin resistant
Enterobacteriaceae
Pseudomonas aeruginosa
Influenza with suspected
secondary pneumococcal
or staphylococcal infection

507

MINI CLINI

Evaluating Persisting Fever
in Pneumonia

Recommended Regimen

PROBLEM:  The RT is caring for a 68-year-old man admitted

Penicillin G or amoxicillin
Ceftriaxone, cefotaxime,
fluoroquinolone, or vancomycin
Second- or third-generation
cephalosporin, azithromycin, or
TMP-SMX
Macrolide ± rifampin or
fluoroquinolone alone
Macrolide or doxycycline
Macrolide or doxycycline

1 week ago with bacteremic H. influenzae pneumonia. His
admitting chest radiograph showed right lower lobe consolidation and a large right pleural effusion. He has a history of
chronic obstructive pulmonary disease (COPD) and reports a
100 pack-year smoking history. He was treated initially with
erythromycin and ceftizoxime until his blood cultures became
positive. The organism was susceptible to ceftizoxime, which
was continued as monotherapy (i.e., treatment with one antibiotic drug). Despite treatment, the patient has remained persistently febrile (39° C) and his chest radiograph has not shown
improvement. Why is he not responding to therapy?

Semisynthetic penicillin ± rifampin
or gentamicin
Vancomycin or linezolid

Third-generation cephalosporin ±
aminoglycoside or carbapenem
Aminoglycoside + antipseudomonal
beta-lactam or carbapenem
Neuraminidase inhibitor (oseltamivir
or zanamivir) and vancomycin or
linezolid

From Mandell MA, Wunderink RG, Anzueto A, et al: Infectious Disease
Society of America/American Thoracic Society consensus guidelines on the
management of community-acquired pneumonia in adults. Clin Infect Dis
44:S27–S72, 2007.
TMP-SMX, Trimethoprim-sulfamethoxazole.

have evolved from the traditional 14 days to a minimum of 5
days of therapy with clinical stability. Exceptions include
Legionnaire’s disease or staphylococcal pneumonia, for which a
minimum of 2 weeks of therapy is recommended. Older individuals and patients with comorbidities also may require longer
courses of treatment. When fever has resolved and patients
begin to improve clinically, oral therapy may be used to complete the treatment program. Failure of the patient’s temperature to normalize within 4 or 5 days suggests a missed pathogen,
a metastatic or closed-space infection (e.g., empyema), drug
fever, or the presence of an obstructing endobronchial lesion.
Empyema should be treated with tube thoracostomy. Abnormal
findings on physical examination may persist beyond 1 week in
20% to 40% of patients, despite clinical improvement. By 1
month, radiographic resolution occurs in 90% of individuals
younger than 50 years.54 After 1 month, radiographic abnormalities may persist in 70% of cases involving older individuals
or in patients with significant underlying illnesses.54

RULE OF THUMB

Empyema should be ruled out in patients with CAP and
a large pleural effusion who fail to respond to therapy.
In cases of CAP, patients often get better before the
chest radiograph shows any improvement.

DISCUSSION:  Patients with CAP who have comorbid ill-

nesses such as alcoholism or COPD may recover more slowly
than healthy individuals despite appropriate therapy. Nevertheless, persistent fever 7 days into optimal treatment should
prompt several considerations.
The two most likely concerns for this patient are (1) an
undrained empyema and (2) an obstructing endobronchial
malignancy, given his substantial smoking history. Other less
likely considerations are drug fever; a new nosocomial infection; a missed pathogen that is not responsive to ceftizoxime,
contributing to his pneumonia; or a deep venous thrombosis
resulting from bed rest.
The next step should be to repeat the history and physical
examination. If these do not reveal a cause of the persistent
fever, a thoracentesis should be performed to exclude empyema.
If thoracentesis findings are negative, further investigation
looking for an endobronchial-obstructing lesion should be
considered.

Health Care–Associated Pneumonia,
Hospital-Acquired Pneumonia, and
Ventilator-Associated Pneumonia
Empiric and definitive therapy of nosocomial pneumonia is
determined by institution-specific data regarding the most
common organisms and their antibiotic-susceptibility profiles
and by patient-specific risk factors. Although general guidelines

have been published,3 the importance of local data cannot be
overemphasized because there is great variation across regions
and across health care facilities regarding the prevalence and
susceptibility profiles of specific pathogens.
Generally, in-hospital aspiration should be treated with a
regimen that provides coverage against anaerobes and gramnegative bacilli, such as a beta-lactam/beta-lactamase inhibitor
combination or clindamycin with a third-generation cephalosporin. Although vancomycin has been the traditional drug of
choice for MRSA pneumonia, evolving data suggest that linezolid may be better than vancomycin. In a randomized controlled trial of vancomycin versus linezolid for treatment of
MRSA pneumonia, clinical resolution of pneumonia occurred
more frequently in patients treated with linezolid, but there was


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SECTION IV  •  Review of Cardiopulmonary Disease

no difference in 60-day mortality between the two groups.55 For
VAP, empiric coverage may be targeted at organisms known to
colonize the patient’s oropharynx or pathogens that are present
in the ICU. Patients with P. aeruginosa pneumonia usually are
treated with two agents, such as a ureidopenicillin or antipseudomonal cephalosporin together with an aminoglycoside or
fluoroquinolone. Other gram-negative pneumonias generally
are treated with a single agent, except in cases involving critically ill patients, for whom a second drug is sometimes added.
If nosocomial legionellosis is present within an institution, a
macrolide may be added to the empiric regimen.
Similar to CAP, the duration of therapy for cases of nosocomial pneumonia is dictated by the clinical course. A study comparing 8 days versus 15 days of therapy in patients with VAP
found that short-course therapy was associated with comparable outcomes to long-course therapy, although the rate of
relapse was slightly higher in patients with Pseudomonas or
Acinetobacter infections.56 More prolonged courses of therapy
may be required in patients who are slow to respond but are

associated with a greater risk for new colonization with other
organisms. Failure of the patient to improve should prompt the
following considerations: the presence of an occult empyema;
an unrecognized pathogen; a new, unrelated nosocomial infection; or other noninfectious causes of fever common in the ICU,
such as deep venous thrombosis, drug fever, occult pancreatitis,
or acalculous cholecystitis (gallbladder inflammation without
gallstones).
The RT has an important role in diagnosing and managing
patients with CAP and nosocomial pneumonia. Helping
patients clear infected secretions aids clinical improvement and
maintaining adequate oxygenation is essential. The usefulness
of chest physiotherapy in the treatment of pneumonia is still
unproved but some patients seem to benefit from it.

PREVENTION
Community-Acquired Pneumonia
Preventive strategies for CAP have focused on immunizing
high-risk individuals against influenza and S. pneumoniae.
Influenza is a risk factor for subsequent development of CAP
during the fall and winter months. In 2010, the Advisory Committee on Immunization Practices (ACIP) expanded its recommendation for influenza vaccination to include all individuals
older than 6 months.57 Immunization is particularly important
for individuals older than 60 years (because it reduces the incidence of illness for this age group by half  58) and for those
with chronic lung or heart disease in whom the morbidity of
influenza may be substantial. Recent studies suggest that widespread immunization of healthy working adults is cost-effective
because the number of sick days taken and the number of visits
to a physician are reduced.59 Health care workers, including RTs,
should be immunized annually to prevent transmission of
influenza to patients.
Currently available pneumococcal vaccines provide protection against the 23 serotypes of S. pneumoniae, which cause

85% to 90% of invasive pneumococcal infections in the United
States. Vaccination is indicated for all individuals older than 65
years and for individuals older than 2 years who have functional
or anatomic asplenia (i.e., lack a spleen). Vaccination is also
indicated in patients with chronic illnesses such as CHF, chronic
lung disease, or chronic liver disease; alcoholism; cerebrospinal
fluid leaks; or conditions characterized by impaired immunity.60
Routine pneumococcal vaccination of all health care workers is
not currently recommended; health care workers who possess
one of the specific indications for vaccination outlined previously should be immunized.
Immunity against Bordetella pertussis fades over time, leading
to transmission from older adults to other adults and infants.
Because secondary bacterial pneumonia occurs in a significant
number of cases of pertussis, the ACIP has recommended
that the tetanus-diphtheria-acellular pertussis (Tdap) vaccine
replace the tetanus-diphtheria (Td) vaccine in the adult immunization schedule.61

Health Care–Associated Pneumonia,
Hospital-Acquired Pneumonia, and
Ventilator-Associated Pneumonia
Preventing nosocomial pneumonia has been intensely studied
over the past 30 years. Table 24-10 summarizes currently available strategies and their relative efficacy. No preventive strategy
is uniformly effective. Many institutions now employ a “ventilator bundle” including several of these measures.
Handwashing is an important but frequently overlooked
measure that can reduce transmission of nosocomial bacteria
from one patient to another. Handwashing is especially important for RTs who may be caring for several ventilated patients
in the ICU. Failure to wash the hands between patient contacts
may result in transmission of respiratory pathogens from one
patient to another. Handwashing is important even if gloves are
worn. Gloves should be changed between patient contacts

because they also can become contaminated with and transmit
bacteria.

TABLE 24-10 
Strategies for Prevention of
Nosocomial Pneumonia
Strategy

Efficacy

Handwashing
Isolation of patients with resistant organisms
Infection control and surveillance
Enteral feeding, rather than total parenteral
nutrition
Semierect position
Sucralfate for bleeding prophylaxis
Careful handling of respiratory therapy
equipment
Subglottic secretion aspiration
Selective digestive decontamination
Topical tracheobronchial antibiotics

Probably effective
Probably effective
Probably effective
Possibly effective
Possibly effective
Possibly effective
Possibly effective

Possibly effective
Unproved efficacy
Unproved efficacy


Pulmonary Infections  •  CHAPTER 24


Infection control surveillance to detect outbreaks of nosocomial pneumonia with specific pathogens and to monitor antibiotic resistance patterns is important. Isolation and caring for
infected patients in the same place can limit the scope and duration of outbreaks, especially in ICUs.
In patients requiring nutrition support, the use of enteral
feeding via jejunostomy has been associated with a lower risk
for nosocomial pneumonia than the use of total parenteral
nutrition.62 In addition, patients who are fed enterally (i.e.,
using the gut to feed) have a lower incidence of pneumonia if
kept semierect rather than recumbent.8
Two studies suggest that GI bleeding prophylaxis with
sucralfate is associated with a lower risk for pneumonia compared with antacid or H2-blockers.63,64 Careful handling of
respiratory therapy equipment may reduce the risk for LRTI in
ventilated patients. Condensate within the tubing may be colonized with bacteria and should be drained away from the
patient because passage of this material into the airway may
encourage colonization with nosocomial pathogens. One study
found that continuous subglottic aspiration of secretions was
effective in reducing the incidence of nosocomial pneumonia
in intubated patients.65 Many studies have failed to show that
selective digestive decontamination is effective to prevent nosocomial pneumonia; this is a strategy that uses topical antibiotics in the oropharynx and GI tract along with a brief course of
systemic therapy. A meta-analysis suggested that topical oral
decontamination may reduce the incidence of VAP but not
mortality, duration of mechanical ventilation, or length of
ICU stay.66

Prevention of nosocomial pneumonia remains a challenge
to the RT. Careful attention to basic infection control practices,
such as frequent handwashing, using new gloves with each
patient contact, and careful handling of respiratory care equipment, is important in preventing nosocomial pneumonia.

TUBERCULOSIS
Tuberculosis, caused by M. tuberculosis, can sometimes mimic
CAP and poses special management challenges for the RT.
Knowledge of the epidemiology, clinical manifestations, diagnosis, infection control management, and treatment of patients
with suspected or proved tuberculosis is essential.

Epidemiology
The epidemiology of tuberculosis in the United States has
changed over the past 25 years. After the introduction of effective drugs to treat tuberculosis in the 1950s, the incidence of
tuberculosis steadily declined. Tuberculosis increasingly became
a disease affecting elderly patients, and most cases represented
reactivation of old latent disease. With the emergence of the
acquired immunodeficiency syndrome (AIDS) epidemic in the
early 1980s, there was a resurgence of tuberculosis in the United
States and worldwide. This resurgence began in 1985 and
peaked in 1992. Since 1992, the incidence of tuberculosis has
declined. This resurgence of tuberculosis was accompanied by
dramatic shifts in the patients at risk and the clinical manifesta-

509

tions of the disease. Multidrug-resistant tuberculosis, defined as
resistance of M. tuberculosis to both isoniazid and rifampin,
emerged as a major public health problem in some populations
and areas. Compared with frequency of the era before AIDS,

tuberculosis now more often occurs in younger individuals with
HIV infection, especially inner-city minority populations with
a history of injection drug use. Foreign-born nationals residing
in the United States have accounted for half of cases reported
annually in recent years.
Tuberculosis has increasingly become a disease affecting
individuals of lower socioeconomic status in whom home­
lessness or crowded living conditions, poor access to health
care, and unemployment have contributed to the persistence of
the disease.67 Other risk factors include the presence of hematologic malignancies, head and neck cancer, celiac disease
(a bowel disease characterized by poor absorption), and the
receipt of medications such as corticosteroids and TNF-alpha
antagonists.67-70

Pathophysiology
Tuberculosis is acquired by inhaling airborne droplets containing the responsible microorganism, M. tuberculosis, and the
lungs are the major site of infection. Microorganism-laden
droplets are deposited in the terminal airways and cause a host
immune response. Most exposed individuals successfully contain the infection and remain asymptomatic, although they
remain at risk for reactivation of infection later in life, especially
if they become immunosuppressed.
Patients with tuberculosis can present with pulmonary or
extrapulmonary manifestations. The major syndromes of pulmonary tuberculosis include primary, reactivation, and endobronchial tuberculosis and tuberculoma.
Primary Tuberculosis
Symptomatic primary tuberculosis occurs in a few individuals
shortly after exposure. Primary tuberculous pneumonia is a
more common clinical presentation in children and in HIVinfected individuals compared with non–HIV-infected adults.
Fever is the most common symptom and occurs in 70% of
patients; it persists for 14 to 21 days on average.71 Chest pain
occurs in approximately 25%; cough is even less common. The

chest radiograph shows hilar lymphadenopathy in 65%, pleural
effusion in 33%, and an infiltrate in approximately 25%. Diagnosis may be difficult given the infrequency of cough and a
pulmonary infiltrate.
Reactivation and Endobronchial
Tuberculosis
Reactivation tuberculosis develops months to years after initial
infection and may occur spontaneously or in the setting of
immunosuppression. In individuals without HIV infection,
reactivation disease accounts for 90% of cases of tuberculosis.
The most common symptoms include fever, cough, night
sweats, and weight loss. Sputum production increases as the
infection progresses and is occasionally accompanied by
hemoptysis, which is seldom massive. Older patients may


510

SECTION IV  •  Review of Cardiopulmonary Disease

present with a more indolent illness in which fever and night
sweats are absent. Physical examination is often unrevealing in
patients with reactivation tuberculosis. Chest radiograph shows
apicoposterior upper lobe disease in 80% to 90% of patients,
and cavities are present in 20% to 40%.
Endobronchial tuberculosis involves the airways and may be
seen in both primary and reactivation tuberculosis. In primary
tuberculosis, hilar nodal enlargement may impinge on the
bronchi, resulting in compression and ultimately ulceration. In
patients with reactivation disease, endobronchial involvement
may occur as a result of direct extension from the parenchyma

or pooling of secretions from upper lobe cavities in the dependent distal airways. Symptoms of endobronchial tuberculosis
include a barking cough in two-thirds of patients, sputum production, wheezing, and hemoptysis. On physical examination,
wheezing is common. The chest radiograph most often shows
an upper lobe cavitary infiltrate with an ipsilateral (i.e., on the
same side) lower lobe infiltrate. Extensive endobronchial disease
may produce bronchiectasis.
Tuberculomas
Tuberculomas are rounded solitary mass lesions and may occur
in primary or reactivation tuberculosis. They are often asymptomatic and may mimic malignancy. Tuberculoma is in the
differential diagnosis of solitary pulmonary nodule and may be
difficult to diagnose without biopsy or excision because expectorated sputum in patients with tuberculoma rarely shows
M. tuberculosis on smear or culture.
Complications
Complications of pulmonary tuberculosis include tuberculous
empyema, bronchiectasis, extensive pulmonary parenchymal
destruction, spontaneous pneumothorax, and massive hemoptysis from rupture of a Rasmussen aneurysm in the wall of a
cavity.
Extrapulmonary Tuberculosis
Extrapulmonary tuberculosis is defined as spread of M. tuberculosis infection beyond the lung and may involve virtually any
organ. The central nervous system, musculoskeletal system,
genitourinary tract, and lymph nodes (scrofula) are the most
common sites of extrapulmonary tuberculosis. HIV-infected
patients who acquire tuberculosis often present with unique
clinical manifestations compared with non–HIV-infected patients. HIV-infected patients may develop rapidly progressive
primary infection and present with both pulmonary and extrapulmonary disease. In patients with advanced AIDS, tuberculosis may manifest as disseminated disease with involvement of
multiple organs, including lymph nodes, bone marrow, liver,
and spleen. Symptoms in this setting include high fevers, sweats,
and progressive weight loss. Findings on examination may
include fever, wasting, and hepatosplenomegaly. Laboratory
testing may show pancytopenia (decreased cell counts in WBCs,

RBCs, and platelets) and advanced immunodeficiency. Imaging
studies often show mediastinal and abdominal lymphadenopathy and hepatosplenomegaly.

Diagnosis
The history is important in diagnosing and managing patients
with suspected tuberculosis. In addition to eliciting the patient’s
symptoms, the clinician should inquire about any history of
tuberculosis, the presence of risk factors for acquiring tuberculosis and/or HIV infection, any history of travel, and potential
contacts with individuals with known or suspected tuberculosis. In patients with a history of tuberculosis, outside medical
records, including drug susceptibility results of prior isolates,
should be obtained. If the patient has been previously treated,
the drugs chosen, duration of treatment, and adherence to
therapy should be evaluated. Risk factors for drug-resistant
tuberculosis should be sought, which include prior treatment
for tuberculosis, exposure to individuals with known drugresistant disease, exposure to individuals with active tuberculosis who have been previously treated, travel to parts of the world
with a high prevalence of drug resistance, or exposure to individuals with active tuberculosis from those areas.
The gold standard for diagnosing tuberculosis from pulmonary and extrapulmonary sites is culture isolation of the organism on solid or liquid media. The major disadvantage of culture
is that M. tuberculosis may take 4 to 6 weeks to grow, thereby
delaying diagnosis. Acid-fast staining of expectorated sputum,
bronchoscopic specimens, and other body fluids or tissues may
be used in patients with suspected pulmonary or extrapulmonary disease. In patients with pulmonary tuberculosis, it is estimated that 104 organisms/ml is required for the smear to be
positive. Acid-fast smears of both sputum and other body sites
are less sensitive than culture for detecting disease. The presence
of acid-fast bacilli on a smear is not synonymous with a diagnosis of M. tuberculosis because nontuberculous mycobacteria
(NTM) can produce pulmonary and extrapulmonary disease in
selected populations. More rapid diagnostic techniques for
identifying M. tuberculosis in clinical specimens and for confirming the identity of the organism in culture are being developed and are available in some centers. These techniques include
nucleic acid amplification, nucleic acid probes, PCR genomic
analysis, and molecular tests for chromosomal mutations associated with drug resistance.
A 5 tuberculin unit purified protein derivative (5 TU PPD)

skin test or interferon-gamma release assay (IGRA) may be
performed in individuals with suspected tuberculosis. Both tests
evaluate for cell-mediated immunity to tuberculosis in individuals with prior exposure to the organism. A PPD consists of
intradermal injection of tuberculin material, which stimulates
a delayed-type hypersensitivity response mediated by T cells
and causes skin induration within 48 to 72 hours. False-positive
results can occur in patients with prior bacille Calmette-Guérin
(BCG) vaccination or infection with NTM species. IGRAs are
blood tests that measure T-cell release of the cytokine interferongamma after stimulation by antigens unique to M. tuberculosis.
IGRAs are unaffected by BCG vaccination status and most NTM
infections (except Mycobacterium marinum and Mycobacterium
kansasii) and require only a single patient encounter, all of
which are advantages over the PPD.72 Both tests become positive


Pulmonary Infections  •  CHAPTER 24


3 to 8 weeks after acquisition of infection. A positive skin test
or IGRA supports the diagnosis in the appropriate clinical
setting, but a negative result does not exclude the diagnosis.
Patients with HIV infection, other causes of immunodeficiency,
advanced age, or other comorbidities may be anergic and unable
to mount either a positive skin test or IGRA result.72,73

Precautions
Patients hospitalized with suspected or proved active pulmonary tuberculosis should be placed in respiratory isolation in
private negative pressure airflow rooms because they pose a risk
for transmitting infection to others by coughing up aerosolized
droplets containing M. tuberculosis. Individuals entering the

patient’s room should wear fit-tested National Institute for
Occupational Safety and Health–approved N-95 or higher
masks or respirators. A surgical mask should be placed on a
patient with suspected or proved active pulmonary tuberculosis
during transport outside the negative pressure room.

Treatment
Treatment recommendations for tuberculosis have been published by the ATS, U.S. Centers for Disease Control and Prevention (CDC), and the IDSA.74 The goals of therapy are to cure
the patient and prevent transmission of M. tuberculosis to
others. Treatment must address clinical and social issues and
should be customized to the patient’s circumstance. At the
outset, daily observed therapy (DOT) should be part of the
treatment program; this consists of observing the patient taking
the antituberculous medications. Treatment programs that use
comprehensive case management and DOT have a higher rate
of successful completion of therapy than other treatment strategies. Social service support, housing assistance, and treatment
for substance abuse may be required for selected individuals
with tuberculosis and should be part of the treatment plan.
Patients with tuberculosis must be promptly reported to the
local department of public health so that contact tracing can be
performed. This includes identification, if possible, of the index
case from whom the patient has contracted the infection and
identification of close personal contacts to whom the patient
may have transmitted M. tuberculosis.
Isoniazid, rifampin, pyrazinamide, and ethambutol are firstline antituberculous medications. Pending antimicrobial susceptibility results, treatment with four drugs at the outset is
recommended. In patients with drug-susceptible pulmonary
tuberculosis, many 6- to 9-month treatment regimens have
been shown to be effective as outlined in guidelines by the ATS,
CDC, and IDSA.74 Patients with multidrug-resistant tuberculosis require more prolonged courses of therapy with multidrug
regimens.

ROLE OF THE RESPIRATORY
THERAPIST IN PULMONARY
INFECTIONS
The RT plays a key role in managing patients with pulmonary
infections, including helping to diagnose and treat the illnesses.

511

Diagnostically, RTs participate in the collection of sputum by
expectoration or assisting physicians during bronchoscopy. In
some settings, RTs may perform mini-BAL.
RTs often administer chest physiotherapy when indicated,
as in patients with bronchiectasis and cystic fibrosis. They
also may be involved in counseling patients in other clearance
techniques, such as autogenic drainage and positive expiratory
pressure (PEP) therapy. RTs also play key roles in modeling
optimal infection control and prevention practices (e.g., handwashing, implementing and complying with respiratory precautions, vaccination) and in advising patients about preventive
interventions, such as influenza, pneumococcal, and Tdap
vaccines.

SUMMARY CHECKLIST
◗ CAP and nosocomial pneumonia are common and

important clinical problems with significant morbidity and
mortality.
◗ S. pneumoniae remains the most common cause of CAP.
Gram-negative bacilli and S. aureus are the most common
causes of nosocomial pneumonia, but their relative
incidence and antimicrobial susceptibility profiles may vary

across institutions.
◗ The mortality risk can be quantified at presentation for
most patients with CAP, which helps in determining the
need for hospitalization.
◗ Routine sputum cultures for patients with CAP must be
interpreted within the context of the sputum Gram stain,
which provides valuable information regarding the
adequacy of the specimen and the predominance of
potential pathogens.
◗ The accurate diagnosis of nosocomial pneumonia remains
a challenge; none of the diagnostic methods currently
available is completely reliable.
◗ Guidelines exist for the treatment of CAP and nosocomial
pneumonia. When possible, pathogen-specific antibiotic
therapy should be used.
◗ Immunizing high-risk individuals against influenza and
S. pneumoniae is the major strategy in preventing CAP.
◗ Strategies for preventing nosocomial pneumonia are not
uniformly effective.
◗ Pulmonary tuberculosis may mimic CAP; the recognition
and appropriate isolation, diagnostic evaluation, and
management of individuals with possible pulmonary
tuberculosis are essential.
◗ The RT can help prevent nosocomial pneumonia by
careful attention to basic infection control procedures
such as handwashing.

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CHAPTER 

25 

Obstructive Lung Disease:
Chronic Obstructive Pulmonary
Disease, Asthma, and Related Diseases
ENRIQUE DIAZ-GUZMAN AND JAMES K. STOLLER

CHAPTER OBJECTIVES
After reading this chapter you will be able to:
◆ State definitions of chronic obstructive pulmonary disease (COPD), asthma, and bronchiectasis.
◆ Understand the major risk factors associated with COPD.
◆ Identify the common signs and symptoms associated with COPD.
◆ Describe a treatment plan for a patient with stable COPD and for a patient with an acute exacerbation of
COPD.
◆ State the typical clinical presentation of a patient with asthma.

◆ Identify the treatment currently available for a patient with acute asthma.
◆ Describe the treatment currently available for patients with bronchiectasis.

CHAPTER OUTLINE
Chronic Obstructive Pulmonary Disease
Overview and Definitions
Epidemiology
Risk Factors and Pathophysiology
Clinical Signs and Symptoms
Management
Establishing the Diagnosis
Optimizing Lung Function
Maximizing Functional Status
Preventing Progression of Chronic Obstructive
Pulmonary Disease and Enhancing Survival
Additional Therapies
Asthma
Definition
Incidence
Etiology and Pathogenesis

Clinical Presentation and Diagnosis
Management
Objective Measurement and Monitoring
Pharmacotherapy
Emergency Department and Hospital Management
Bronchial Thermoplasty
Immunotherapy
Environmental Control
Patient Education

Special Considerations in Asthma Management
Bronchiectasis
Clinical Presentation
Evaluation
Management
Role of the Respiratory Therapist in Obstructive
Lung Disease

KEY TERMS
acute exacerbation of COPD
airway hyperresponsiveness
airway inflammation
airway obstruction
asthma

514

bronchiectasis
bronchodilator
bronchospasm
chronic bronchitis

cystic fibrosis
emphysema
noninvasive ventilation
supplemental oxygen


Obstructive Lung Disease  •  CHAPTER 25

T

he category of obstructive lung diseases is broad
and includes chronic obstructive pulmonary disease
(COPD) and asthma as the most common diseases and
bronchiectasis and cystic fibrosis as less common forms.
Airflow obstruction also may be a feature of other lung diseases
such as sarcoidosis, lymphangioleiomyomatosis, and congestive
heart failure. This chapter reviews the major obstructive lung
diseases, emphasizing their defining features, epidemiology,
pathophysiology, clinical signs and symptoms, prognosis, and
management. Cystic fibrosis is discussed in Chapter 34.

Chronic
bronchitis

Emphysema
1

Similarly, the GOLD guidelines define COPD as follows2:
A disease state characterized by persistent airflow limitation that
is usually progressive, and is associated with an enhanced
inflammatory response in the airways and the lung to noxious
particles or gases. Exacerbations and comorbidities contribute to
the overall severity in individual patients.

The spectrum of COPD is shown in Figure 25-1, which
presents a nonproportional Venn diagram representing the

major components of COPD—chronic bronchitis and emphysema. Although asthma is no longer conventionally considered
to be part of the spectrum of COPD, the diagram shows that
there is overlap between asthma and COPD. In actual practice,
it may not be possible to distinguish between individuals with
a history of asthma but with incompletely reversible airflow
obstruction and individuals with COPD.
The two major diseases that make up COPD—emphysema
and chronic bronchitis—are defined in different ways. Emphysema is defined in anatomic terms as a condition characterized
by abnormal, permanent enlargement of the airspaces beyond
the terminal bronchiole, accompanied by destruction of the
walls of the airspaces without fibrosis. Chronic bronchitis is
defined in clinical terms as a condition in which chronic pro-

COPD

5

3

4
8
6

7
10
9

Airflow
obstruction

Overview and Definitions

Chronic obstructive pulmonary disease (COPD) is a preventable
and treatable disease state characterized by airflow limitation
that is not fully reversible. The airflow limitation is usually
progressive and is associated with an abnormal inflammatory
response of the lungs to noxious particles or gases, primarily
caused by cigarette smoking. Although COPD affects the lungs, it
also produces significant systemic consequences.

2

11

CHRONIC OBSTRUCTIVE
PULMONARY DISEASE
The term chronic obstructive pulmonary disease (COPD), or
sometimes chronic obstructive lung disease (COLD), refers to a
disease state characterized by the presence of incompletely
reversible airflow obstruction. Current guidelines by the American Thoracic Society (ATS) and the Global Initiative for Chronic
Obstructive Lung Disease (GOLD) guidelines recommend the
use of the term COPD to encompass both chronic bronchitis
and emphysema. The ATS guidelines statement regarding
COPD defines this entity as follows1:

515

Asthma

FIGURE 25-1  Schema of chronic obstructive pulmonary disease

(COPD). This nonproportional Venn diagram shows subsets of
patients with chronic bronchitis, emphysema, and asthma. The
subsets constituting COPD are shaded. Subset areas are not
proportional to actual relative subset sizes. Asthma is by definition
associated with reversible airflow obstruction, although in variant
asthma special maneuvers may be necessary to make the
obstruction evident. Patients with asthma whose airflow obstruction
is completely reversible (subset 9) are not considered to have
COPD. Because in many cases it is virtually impossible to
differentiate patients with asthma whose airflow obstruction does
not remit completely from patients with chronic bronchitis and
emphysema who have partially reversible airflow obstruction with
airway hyperreactivity, patients with unremitting asthma are
classified as having COPD (subsets 6, 7, and 8). Chronic bronchitis
and emphysema with airflow obstruction usually occur together
(subset 5), and some patients may have asthma associated with
these two disorders (subset 8). Individuals with asthma who are
exposed to chronic irritation, as from cigarette smoke, may develop
a chronic, productive cough, a feature of chronic bronchitis (subset
6). Such patients are often referred to as having asthmatic
bronchitis or the asthmatic form of COPD. Individuals with chronic
bronchitis or emphysema without airflow obstruction (subsets 1, 2,
and 11) are not classified as having COPD. Patients with airway
obstruction caused by diseases with a known cause or specific
pathologic process, such as cystic fibrosis or obliterative
bronchiolitis (subset 10), are not included in this definition.

ductive cough is present for at least 3 months per year for at
least 2 consecutive years. The definition specifies further that
other causes of chronic cough (e.g., gastroesophageal reflux,

asthma, and postnasal drip) have been excluded. Figure 25-1
shows considerable overlap between chronic bronchitis and
emphysema and some overlap with asthma—that is, when
airflow obstruction is incompletely reversible. Figure 25-1 also
shows that chronic bronchitis and emphysema can occur
without airflow obstruction, although the clinical significance
of these diseases usually comes from obstruction to airflow.

Epidemiology
COPD is one of the most frequent causes of morbidity and
mortality worldwide.3 The World Health Organization predicts


516

SECTION IV  •  Review of Cardiopulmonary Disease

that COPD will become the fifth most prevalent disease in the
world and the third leading cause of worldwide mortality by
2030. In the United States, COPD is currently the third leading
cause of death; it was responsible for 134,676 deaths and 715,000
hospitalizations in 2010.4 Estimates suggest that 24 million
Americans are affected, though only 15 million U.S. adults have
been diagnosed.4-6 Data from the National Health and Nutrition
Examination Survey (NHANES) suggest that among adults 25
to 75 years old in the United States, mild COPD (defined as
forced expiratory volume in 1 second [FEV1]/forced vital capacity [FVC] < 70%, and FEV1 > 80% predicted) occurs in 6.9%
and moderate COPD (defined as FEV1/FVC < 79% and FEV1 ≤
80% predicted) occurs in 6.6%.3 COPD prevalence increases
with aging, with a five-fold increased risk for adults older than

65 years compared with adults younger than 40 years, and some
studies estimate a prevalence of 20% to 30% in adults older
than 70 years.7
The growing health burden from COPD is caused in part by
the aging of the population but mainly by the continued use of
tobacco. The socioeconomic burden of COPD is also substantial. In 2010, COPD caused 715,000 hospitalizations (which
accounted for 1.9% of all hospitalizations in the United States),
and, in 2010, COPD resulted in a total health expenditure of
$49.9 billion.4 In this regard, COPD is a problem that is a frequent challenge for the respiratory clinician.

Risk Factors and Pathophysiology
Although many risk factors exist for COPD (Box 25-1), the two
most common are cigarette smoking (which has been estimated
to account for 80% to 90% of all COPD-related deaths) and
alpha-1 antitrypsin (AAT) deficiency.8 Evidence linking cigarette

smoking to the development of COPD is strong and includes
the following:
• Symptoms of COPD (e.g., chronic cough and phlegm
production) are more common in smokers than in
nonsmokers.
• Impaired lung function with evidence of an obstructive
pattern of lung dysfunction is more common in smokers
than in nonsmokers.
• Pathologic changes of airflow obstruction and chronic bronchitis are evident in the lungs of smokers.
• So-called susceptible smokers, who represent approximately
15% of all cigarette smokers, experience more rapid rates of
decline of lung function than nonsmokers.
Information from the Lung Health Study (Figure 25-2) highlighted the accelerated rate of decrease of FEV1 in smokers
compared with former smokers who have achieved sustained

quitting.9,10 Overall, the strength of evidence implicating cigarette smoking as a cause of COPD has allowed the U.S. Surgeon
General to conclude, “Cigarette smoking is the major cause of
chronic obstructive lung disease in the United States for both
men and women. The contribution of cigarette smoking to
chronic obstructive lung disease morbidity and mortality far
outweighs all other factors.”11
As the second well-recognized cause of emphysema, AAT
deficiency, sometimes called genetic emphysema or alpha-1 antiprotease deficiency, is a condition that features a reduced amount
of the protein alpha-1 antitrypsin (AAT), which may result in
the early onset of emphysema and which is inherited as a
so-called autosomal codominant condition. AAT deficiency

Box 25-1

Causes of Chronic Obstructive
Pulmonary Disease*

COMMON CAUSES
•
•
•
•
•

Cigarette smoking
Alpha-1 antitrypsin (AAT) deficiency
Outdoor air pollution
Long-standing asthma
Biomass and occupational exposure (e.g., chronic exposure
to wood smoke with poorly ventilated indoor cooking)

LESS COMMON CAUSES
•
•
•
•
•
•
•
•
•

Hypocomplementemic urticarial vasculitis
Intravenous methylphenidate (Ritalin) abuse
Ehlers-Danlos syndrome
Marfan syndrome
Cutix laxa
Menke syndrome
Salla disease†
Alpha-1 antichymotrypsin deficiency†
Human immunodeficiency virus infection (emphysema-like
illness)

*Multiple causes (e.g., cigarette smoking and alpha-1 antitrypsin
deficiency) may coexist in a single patient.
†
Putative cause; firm evidence is unavailable.

Postbronchodilator FEV1, L

2.9

Sustained quitters

2.8

2.7

Continuing smokers

2.6

2.5

2.4
Screen 2

1

2

3

4

5

Follow-up, yr

FIGURE 25-2  Mean postbronchodilator FEV1 for participants in

the smoking intervention and placebo groups who were sustained
quitters (red circles) and continuing smokers (purple circles). The
two curves diverge sharply after baseline. (From Anthonisen SR,
Connett JE, Kiley JP, et al: Effects of smoking intervention and the
use of an anticholinergic bronchodilator on the rate of decline of
FEV1: the Lung Health Study. JAMA 272:1497–1504, 1994.)




Obstructive Lung Disease  •  CHAPTER 25

accounts for 2% to 3% of all cases of COPD and affects 100,000
Americans but is underrecognized by health care providers. In
one 1995 survey, the mean interval between the first onset of
pulmonary symptoms and initial diagnosis of AAT deficiency
was 7.2 years, and 43% of individuals with severe deficiency
of AAT reported seeing at least three physicians before the
diagnosis of AAT deficiency was first made.12 More recent
studies suggest that underrecognition of AAT deficiency persists
and that the diagnostic delay interval has not decreased
significantly.12-15
Identifying individuals with AAT deficiency is simple, often
requiring only a blood test of the serum AAT level. Respiratory
therapists (RTs) can contribute importantly to detecting individuals with AAT deficiency (e.g., by suggesting or offering
testing when airflow obstruction is diagnosed in the pulmonary
function laboratory by an RT performing the test and by making
patients aware of available free, home-based testing kits) (see
). Several observations suggest the importance of detection: (1) first-degree relatives (e.g.,
siblings, parents, and children) also may be affected but unaware

of their risk; (2) early detection allows appropriate monitoring
and therapy, including the very important step of smoking cessation; and (3) for individuals with established emphysema,
consideration can be given to available specific therapy, called
intravenous augmentation therapy (which is the administration
of purified AAT intravenously to individuals with severe deficiency of AAT). The risk for developing emphysema for individuals with AAT deficiency increases as the serum AAT level
decreases to less than 11 µmol/L, or less than approximately
57 mg/dl using a testing technique called nephelometry; these
levels in serum define the so-called protective threshold value,
which is the serum level below which the risk for emphysema
is felt to increase. Cigarette smoking markedly accelerates
the rate of emphysema progression in individuals with AAT
deficiency.14
Study of AAT deficiency has helped formulate the proteaseantiprotease hypothesis of emphysema.14,16 In this explanatory
model (Figure 25-3), lung elastin, a major structural protein
that supports the alveolar walls of the lung, is normally protected by AAT, a protein that defends the lung against tissue
destruction by neutrophil elastase. Neutrophil elastase is a
protein contained within a category of white blood cells called
neutrophils that is released when neutrophils are attracted to
the lung during inflammation or infection. Under normal circumstances of an adequate amount of AAT, neutrophil elastase
is counteracted so as not to digest lung elastin. However, in the
face of a severe deficiency of AAT (i.e., when serum levels
decrease below the “protective threshold” serum value of
11 µmol/L, or 57 mg/dl), neutrophil elastase may go unchecked,
causing breakdown of elastin and of alveolar walls. This
protease-antiprotease model explains the pathogenesis of
emphysema in AAT deficiency, but evidence suggesting its role
in COPD in individuals with normal amounts of AAT is conflicting. Also, other enzymes that break down proteins (e.g.,
matrix metalloproteinases) are thought to contribute to the
destruction of alveolar walls that produces emphysema.17

517

III
Depresses

IV
Oxidant-Scavengers
protect?

Antielastases

O
MET S reductase
reactivates?

Block
Lung elastin
Destroy

Repairs

Elastases

New
synthesis

Augments

Depresses?

I

II

FIGURE 25-3  Proposed biochemical links between cigarette
smoking and the pathogenesis of emphysema. (I) Smoking recruits
monocytes, macrophages, and (through macrophage chemotactic
factors) polymorphonuclear neutrophils to the lung, elevating
the connective tissue “burden” of elastolytic serine and
metalloproteases. (III) At the same time, oxidants in smoke plus
oxidants produced by smoke-stimulated lung phagocytes (and
oxidizing products of chemical interactions between these two)
inactivate bronchial mucus proteinase inhibitor and alpha-1
antitrypsin (AAT), the latter representing the major antielastase
“shield” of the respiratory units. (II) Other, unidentified water-soluble,
gas-phase components of cigarette smoke (cyanide, copper
chelators) inhibit lysyl oxidase–catalyzed oxidative deamination of
epsilon-amino groups in tropoelastin and block formation of
desmosine and presumably other cross-links during elastin
synthesis, decreasing connective tissue repair. (IV) Antioxidants
(ceruloplasmin, methionine-sulfoxide-reductase) may protect or
reactivate elastase inhibitors, and other unidentified factors may
modulate the chemical lesions induced in the lung by smoking to
influence the risk for developing COPD. (Modified from Janoff A,
Carp H, Laurent P, et al: The role of oxidative processes in
emphysema. Am Rev Respir Dis 127[Suppl]:S31, 1983.)

COPD may occur without active cigarette smoking or AAT
deficiency (see Box 25-1).18,19 Factors such as passive smoking,
air pollution, occupational exposure, and airway hyperresponsiveness may contribute to airflow obstruction that is not

reversible.
The mechanisms of airflow obstruction in COPD include
inflammation and obstruction of small airways (<2 mm in
diameter); loss of elasticity, which keeps small airways open
when elastin is destroyed in emphysema; and active bronchospasm. Although traditionally considered to be characteristic
of asthma, some reversibility of airflow obstruction has been
observed in up to two-thirds of patients with COPD when
tested multiple times with inhaled bronchodilators.20

Clinical Signs and Symptoms
Common symptoms of COPD include cough, phlegm production, wheezing, and shortness of breath, typically on exertion.
Dyspnea is often slow but progressive in onset and occurs later
in the course of the disease, characteristically in the late sixth
or seventh decade of life. One notable exception is AAT